Methyl- and trifluoromethyl-substituted pyrrolopyridine modulators of RORC2 and methods of use thereof

ABSTRACT

The present invention provides methyl- and trifluoromethyl-substituted pyrrolopyridines, pharmaceutical compositions thereof, methods of modulating RORγ activity and/or reducing the amount of IL-17 in a subject, and methods of treating various medical disorders using such pyrrolopyridines and pharmaceutical compositions thereof.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/055,811, filed Sep. 26, 2014; U.S. ProvisionalPatent Application Ser. No. 62/110,048, filed Jan. 30, 2015; and U.S.Provisional Patent Application Ser. No. 62/209,124, filed Aug. 24, 2015,the disclosures of all three of which are hereby incorporated byreference in their entireties.

BACKGROUND OF THE INVENTION

Retinoid-related orphan receptors (ROR) are reported to have animportant role in numerous biological processes. Scientificinvestigations relating to each of retinoid-related orphan receptorsRORα, RORβ, and RORγ have been described in the literature. Continuingresearch in this field is spurred by the promise of developing newtherapeutic agents to treat medical disorders associated withretinoid-related orphan receptor activity.

RORγ has been reported to be expressed in high concentration in varioustissues, such as thymus, kidney, liver, muscle, and certain fat tissue.Two isoforms of RORγ have been identified and are referred to as γ1 andγ2 (also referred to as RORγt). Expression of the γ2 isoform has beenreported to appear in, for example, double-positive thymocytes.Compounds capable of modulating RORγt activity are contemplated toprovide a therapeutic benefit in the treatment of multiple medicaldisorders, including immune and inflammatory disorders.

Numerous immune and inflammatory disorders continue to afflict millionsof patients worldwide. Significant advances have been made in treatingthese disorders. However, current therapies do not provide satisfactoryresults for all patients due to, for example, detrimental side effectsor insufficient efficacy. Treatments for immune and inflammatorydisorders vary depending on the particular medical disorder, and ofteninvolve use of immunosuppressive drugs. Surgery (e.g., splenectomy),plasmapheresis, or radiation can be used in certain instances.

One exemplary immune disorder in need of better therapy is psoriasis.Psoriasis is a T cell-mediated inflammatory disease that affectsapproximately 2% to 3% of adults and has a substantial adverse impact onthe quality of life for patients suffering from this disorder. Plaquesresulting from psoriasis can be painful and are visually unappealing.Various therapeutics have been developed in an attempt to treatpsoriasis. However, the traditional therapies for psoriasis often havetoxic adverse effects. Accordingly, a need exists for improvedtreatments for psoriasis as well as other immune and inflammatorydisorders.

SUMMARY

The present invention provides compounds, pharmaceutical compositions,methods of inhibiting RORγ activity and/or reducing the amount of IL-17in a subject, and methods of treating various medical disorders usingsuch compounds. In particular, one aspect of the invention relates tocompounds represented by Formula I:

and pharmaceutically acceptable salts, pharmaceutically activemetabolites, pharmaceutically acceptable prodrugs, and pharmaceuticallyacceptable solvates thereof; wherein R¹, X, Y and W are as defined inthe Detailed Description.

Another aspect of the invention provides a method of treating a subjectsuffering from a medical disorder. The method comprises administering tothe subject a therapeutically effective amount of a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof, as describedin the Detailed Description. A large number of disorders may be treatedusing the compounds described herein. For example, the compoundsdescribed herein may be used to treat an immune disorder or inflammatorydisorder, such as rheumatoid arthritis, psoriasis, chronicgraft-versus-host disease, acute graft-versus-host disease, Crohn'sdisease, inflammatory bowel disease, multiple sclerosis, systemic lupuserythematosus, Celiac Sprue, idiopathic thrombocytopenic thromboticpurpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerativecolitis, asthma, epidermal hyperplasia, and other medical disordersdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray crystal structure (ORTEP drawing) of1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one.

FIG. 2 is an X-ray crystal structure (ORTEP drawing) of (S)-tert-butyl4-(5-amino-1-methyl-4-(methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate.The three intramolecular C—H . . . O hydrogen bonds are drawn as thindashed lines.

DETAILED DESCRIPTION

The invention provides compounds, pharmaceutical compositions, methodsof modulating RORγ activity and/or reducing the amount of IL-17 in asubject, and therapeutic uses of said compounds and pharmaceuticalcompositions. The practice of the present invention employs, unlessotherwise indicated, conventional techniques of organic chemistry,pharmacology, molecular biology (including recombinant techniques), cellbiology, biochemistry, and immunology. Such techniques are explained inthe literature, such as in “Comprehensive Organic Synthesis” (B. M.Trost & I. Fleming, eds., 1991-1992); “Handbook of experimentalimmunology” (D. M. Weir & C. C. Blackwell, eds.); “Current protocols inmolecular biology” (F. M. Ausubel et al., eds., 1987, and periodicupdates); and “Current protocols in immunology” (J. E. Coligan et al.,eds., 1991), each of which is herein incorporated by reference in itsentirety.

Various aspects of the invention are set forth below in sections;however, aspects of the invention described in one particular sectionare not to be limited to any particular section. Further, when avariable is not accompanied by a definition, the previous definition ofthe variable controls.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods and compositions described herein,which will be limited only by the appended claims.

All publications and patents mentioned herein are incorporated herein byreference in their entirety for the purpose of describing anddisclosing, for example, the constructs and methodologies that aredescribed in the publications, which might be used in connection withthe methods, compositions and compounds described herein.

Chemical names, common names, and chemical structures may be usedinterchangeably to describe the same structure. If a chemical compoundis referred to using both a chemical structure and a chemical name, andan ambiguity exists between the structure and the name, the structurepredominates.

DEFINITIONS

“ROR” stands for Retinoic acid receptor-related Orphan Receptor. Thereare three forms of ROR, ROR-α, -β, and -γ and each is encoded by aseparate gene (RORA, RORB, and RORC respectively). There are twosubtypes of RORC: 1 and 2. Subtype 2 is also called “t”. The human RORCgene is also called TOR; RORG; RZRG; NRIF3; and RZR-GAMMA. The humanprotein RORC is also called nuclear receptor ROR-gamma; nuclear receptorRZR-gamma; retinoic acid-binding receptor gamma; retinoid-related orphanreceptor gamma; RAR-related orphan receptor C, isoform a; RAR-relatedorphan nuclear receptor variant 2; nuclear receptor subfamily 1 group Fmember 3. As used herein, “RORγ” and “RORC2” are used interchangeably torefer to a protein from a RORC subtype 2 gene.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

The term “alkyl” refers to a substituent obtained by removing a hydrogenfrom a saturated, straight (i.e. unbranched) or branched carbon chain(or carbon), or combination thereof, which has the number of carbonatoms designated (i.e. C₁-C₆ means one to six carbons). Examples ofalkyl substituents include methyl, ethyl, propyl (including n-propyl andisopropyl), butyl (including n-butyl, isobutyl, sec-butyl andtert-butyl), pentyl, isoamyl, hexyl and the like.

The term “haloalkyl” is an alkyl in which at least one hydrogen on thealkyl is replaced with a halogen atom. In certain embodiments in whichtwo or more hydrogen atoms are replaced with halogen atoms, the halogenatoms are all the same as one another. In other embodiments in which twoor more hydrogen atoms are replaced with halogen atoms, the halogenatoms are not all the same as one another.

The term “cycloalkyl” refers to a substituent obtained by removing ahydrogen atom from a saturated carbocycle having the number of carbonatoms designated (i.e. C₃-C₈ means three to eight carbons). Cycloalkylrefers to both a radical of a single ring saturated carbocycle, such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. as well as aradical of a two or three ring bridged, fused or spiro saturatedcarbocycle, such as bicyclo[4.2.0]octane and decalinyl.

This specification uses the terms “substituent,” “radical,” and “group”interchangeably.

If a group of substituents are collectively described as beingoptionally substituted by one or more of a list of substituents, thegroup may include: (1) unsubstitutable substituents, (2) substitutablesubstituents that are not substituted by the optional substituents,and/or (3) substitutable substituents that are substituted by one ormore of the optional substituents.

If a substituent is described such that it “may be substituted” or asbeing “optionally substituted” with up to a particular number ofnon-hydrogen substituents, that substituent may be either (1) notsubstituted; or (2) substituted by up to that particular number ofnon-hydrogen substituents or by up to the maximum number ofsubstitutable positions on the substituent, whichever is less. Thus, forexample, if a substituent is described as a heteroaryl optionallysubstituted with up to 3 non-hydrogen substituents, then any heteroarylwith less than 3 substitutable positions would be optionally substitutedby up to only as many non-hydrogen substituents as the heteroaryl hassubstitutable positions. To illustrate, tetrazolyl (which has only onesubstitutable position) would be optionally substituted with up to onenon-hydrogen substituent. To illustrate further, if an amino nitrogen isdescribed as being optionally substituted with up to 2 non-hydrogensubstituents, then the nitrogen will be optionally substituted with upto 2 non-hydrogen substituents if the amino nitrogen is a primarynitrogen, whereas the amino nitrogen will be optionally substituted withup to only 1 non-hydrogen substituent if the amino nitrogen is asecondary nitrogen.

As used herein compounds of Formula I may be referred to as a“compound(s) of the invention.” Such terms are also defined to includeall forms of the Formula I including hydrates, solvates, isomers,crystalline and non-crystalline forms, isomorphs, polymorphs, andmetabolites thereof. For example, the compounds of Formula I andpharmaceutically acceptable salts thereof, may exist in unsolvated andsolvated forms. When the solvent or water is tightly bound, the complexwill have a well-defined stoichiometry independent of humidity. When,however, the solvent or water is weakly bound, as in channel solvatesand hygroscopic compounds, the water/solvent content will be dependenton humidity and drying conditions. In such cases, non-stoichiometry willbe the norm.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes, such as, oxidation reactions) by which aparticular substance is changed by an organism. Thus, enzymes mayproduce specific structural alterations to a compound. For example,cytochrome P450 catalyzes a variety of oxidative and reductive reactionswhile uridine diphosphate glucuronyl transferases catalyze the transferof an activated glucuronic-acid molecule to aromatic alcohols, aliphaticalcohols, carboxylic acids, amines and free sulfhydryl groups. Furtherinformation on metabolism may be obtained from The Pharmacological Basisof Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein can be identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds. Both methods are well known in the art. In someembodiments, metabolites of a compound are formed by oxidative processesand correspond to the corresponding hydroxy-containing compound. In someembodiments, a compound is metabolized to pharmacologically activemetabolites.

In some embodiments, compounds described herein could be prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, apharmaceutically active compound is modified such that the activecompound will be regenerated upon in vivo administration. The prodrugcan be designed to alter the metabolic stability or the transportcharacteristics of a drug, to mask side effects or toxicity, to improvethe flavor of a drug or to alter other characteristics or properties ofa drug. By virtue of knowledge of pharmacodynamic processes and drugmetabolism in vivo, those of skill in this art, once a pharmaceuticallyactive compound is known, can design prodrugs of the compound. (see, forexample, Nogrady (1985) Medicinal Chemistry A Biochemical Approach,Oxford University Press, New York, pages 388-392; Silverman (1992), TheOrganic Chemistry of Drug Design and Drug Action, Academic Press, Inc.,San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic andMedicinal Chemistry Letters, Vol. 4, p. 1985).

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a derivative as set forth herein areincluded within the scope of the claims. In some cases, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. Prodrugs may be designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In some embodiments, the design of a prodrugincreases the effective water solubility. See, e.g., Fedorak et al., Am.J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein in their entirety.

The compounds of the invention may have asymmetric carbon atoms. Thecarbon-carbon bonds of the compounds of the invention may be depictedherein using a solid line, a solid wedge or a dotted wedge. The use of asolid line to depict bonds to asymmetric carbon atoms is meant toindicate that all possible stereoisomers (e.g. specific enantiomers,racemic mixtures, etc.) at that carbon atom are included. The use ofeither a solid or dotted wedge to depict bonds to asymmetric carbonatoms is meant to indicate that only the stereoisomer shown is meant tobe included. It is possible that compounds of the invention may containmore than one asymmetric carbon atom. In those compounds, the use of asolid line to depict bonds to asymmetric carbon atoms is meant toindicate that all possible stereoisomers are meant to be included. Forexample, unless stated otherwise, it is intended that the compounds ofthe invention can exist as enantiomers and diastereomers or as racematesand mixtures thereof. The use of a solid line to depict bonds to one ormore asymmetric carbon atoms in a compound of the invention and the useof a solid or dotted wedge to depict bonds to other asymmetric carbonatoms in the same compound is meant to indicate that a mixture ofdiastereomers is present.

Stereoisomers of compounds of the invention include cis and transisomers, optical isomers such as R and S enantiomers, diastereomers,geometric isomers, rotational isomers, conformational isomers, andtautomers of the compounds of the invention, including compoundsexhibiting more than one type of isomerism; and mixtures thereof (suchas racemates and diastereomeric pairs). Also included are acid additionor base addition salts wherein the counterion is optically active, forexample, D-lactate or L-lysine, or racemic, for example, DL-tartrate orDL-arginine.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in Formula I herein, but for thefact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that may be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but notlimited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and³⁶Cl. Certain isotopically-labeled compounds of Formula I, for examplethose into which radioactive isotopes such as ³H and ¹⁴O areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴O, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically-labeled compounds the invention may generally be preparedby carrying out the procedures disclosed in the Schemes and/or in theExemplification below, by substituting an isotopically-labeled reagentfor a non-isotopically-labeled reagent.

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound may be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically acceptable. The term “pharmaceutically acceptable salt”refers to a salt prepared by combining a compound of Formula I with anacid whose anion, or a base whose cation, is generally consideredsuitable for human consumption. Pharmaceutically acceptable salts areparticularly useful as products of the methods of the present inventionbecause of their greater aqueous solubility relative to the parentcompound. For use in medicine, the salts of the compounds of thisinvention are non-toxic “pharmaceutically acceptable salts.” Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention which are generallyprepared by reacting the free base with a suitable organic or inorganicacid.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric,boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic,sulfonic, and sulfuric acids, and organic acids such as acetic,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isothionic, lactic, lactobionic, maleic, malic,methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic,tartaric, and trifluoroacetic acids. Suitable organic acids generallyinclude but are not limited to aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic, and sulfonic classes of organicacids.

Specific examples of suitable organic acids include but are not limitedto acetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartaric acid, citrate,ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid,galactarate, galacturonate, adipate, alginate, butyrate, camphorate,camphorsulfonate, cyclopentanepropionate, dodecylsulfate,glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate,picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, i.e., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In anotherembodiment, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine, olamine, tromethamine and zincsalts.

Organic salts may be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-benzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (i.e., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (i.e.,benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, forexample, hemisulphate and hemicalcium salts.

Compounds

In the following description of compounds suitable for use in themethods described herein, definitions of referred-to standard chemistryterms may be found in reference works (if not otherwise defined herein),including Carey and Sundberg “Advanced Organic Chemistry 4th Ed.” Vols.A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, proteinchemistry, biochemistry, recombinant DNA techniques and pharmacology,within the ordinary skill of the art are employed. Unless specificdefinitions are provided, the nomenclature employed in connection with,and the laboratory procedures and techniques of, analytical chemistry,synthetic organic chemistry, and medicinal and pharmaceutical chemistrydescribed herein are those known in the art. Standard techniques can beused for chemical syntheses, chemical analyses, pharmaceuticalpreparation, formulation, and delivery, and treatment of patients.

In certain embodiments, the compounds of the invention described hereinare selective for RORγ over RORα and/or RORβ.

Generally, an inhibitor compound of RORγ used in the methods describedherein is identified or characterized in an in vitro assay, e.g., anacellular biochemical assay or a cellular functional assay. Such assaysare useful to determine an in vitro IC₅₀ for said compounds. In someembodiments, the RORγ inhibitor compound used for the methods describedherein inhibits RORγ activity with an in vitro IC₅₀ of less than 25 μM(e.g., less than 20 μM, less than 10 μM, less than 1 μM, less than 0.5μM, less than 0.4 μM, less than 0.3 μM, less than 0.1, less than 0.08μM, less than 0.06 μM, less than 0.05 μM, less than 0.04 μM, less than0.03 μM, less than less than 0.02 μM, less than 0.01, less than 0.008μM, less than 0.006 μM, less than 0.005 μM, less than 0.004 μM, lessthan 0.003 μM, less than less than 0.002 μM, less than 0.001, less than0.00099 μM, less than 0.00098 μM, less than 0.00097 μM, less than0.00096 μM, less than 0.00095 μM, less than 0.00094 μM, less than0.00093 μM, less than 0.00092, or less than 0.00090 μM). In someembodiments, the RORγ inhibitor compound is a compound described in theExemplification.

Described herein are compounds of Formula I. Also described herein arepharmaceutically acceptable salts, pharmaceutically acceptable solvates,pharmaceutically active metabolites, and pharmaceutically acceptableprodrugs of such compounds. Pharmaceutical compositions that include atleast one such compound or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, pharmaceutically active metaboliteor pharmaceutically acceptable prodrug of such compound, are provided.In some embodiments, when compounds disclosed herein contain anoxidizable nitrogen atom, the nitrogen atom can be converted to anN-oxide by methods well known in the art. In certain embodiments,isomers and chemically protected forms of compounds having a structurerepresented by Formula I are also provided.

One aspect of the invention relates to a compound of Formula I:

or a pharmaceutically acceptable salt, pharmaceutically activemetabolite, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, wherein,

Y is —CH₃ or —CF₃;

X is phenyl optionally substituted with one, two, three, four or fivesubstituents independently selected from the group consisting of —CH₃,—CH₂CH₃, —CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃,—F, —Cl, —Br and —CN;

R¹ is —CH₃ or —CH₂CH₃;

W is

each optionally substituted with one, two, three, four or five —CH₃; and

R² is (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl, tetrahydrothiophenyl,thietanyl or indanyl, optionally substituted with one, two, three, fouror five substitutents independently selected for each occurrence fromthe group consisting of —F, —Cl, —Br, —OH, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl and (C₃-C₈)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, provided that when Y is —CH₃, X is

R¹ is —CH₃ and W is

then R² is not

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R¹ is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R¹ is —CH₂CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; and R¹is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W

optionally substituted with one, two, three, four or five —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; and R¹is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; and R¹is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; and R¹is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; and R¹is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; and R¹is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

optionally substituted with one, two, three, four or five —CH₃; R¹ is—CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

and R¹ is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

substituted with one —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

and R¹ is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

and R¹ is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

and R¹ is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

and R¹ is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

substituted with two —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

and R¹ is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

and R¹ is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein W is

R¹ is —CH₃; and Y is —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is unsubstituted phenyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is phenyl substituted with one, two,three, four or five substituents independently selected from the groupconsisting of —CH₃, —CH₂CH₃, —CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃,—OCH₂CH₂OH, —OCH₂CH₂OCH₃, —F, —Cl, —Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is phenyl substituted with onesubstituent selected from the group consisting of with —CH₃, —CH₂CH₃,—CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃, —F, —Cl,—Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is phenyl substituted with twosubstituents independently selected from the group consisting of —CH₃,—CH₂CH₃, —CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃,—F, —Cl, —Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is phenyl substituted with threesubstituents independently selected from the group consisting of —CH₃,—CH₂CH₃, —CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃,—F, —Cl, —Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is phenyl substituted with foursubstituents independently selected from the group consisting of —CH₃,—CH₂CH₃, —CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃,—F, —Cl, —Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is phenyl substituted with fivesubstituents independently selected from the group consisting of —CH₃,—CH₂CH₃, —CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃,—F, —Cl, —Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is phenyl substituted with —CN andoptionally substituted with one or two substituents independentlyselected from the group consisting of —CH₃, —CH₂CH₃, —CH₂OH, —OH, —OCH₃,—SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃, —F, —Cl, —Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is phenyl substituted with —CI andoptionally substituted with one or two substituents independentlyselected from the group consisting of —CH₃, —CH₂CH₃, —CH₂OH, —OH, —OCH₃,—SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃, —F, —Cl, —Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

optionally substituted with one additional substituent selected from thegroup consisting of —CH₃, —CH₂CH₃, —CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃,—OCH₂CH₂OH, —OCH₂CH₂OCH₃, —F, —Cl, —Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

substituted with one additional substituent selected from the groupconsisting of —CH₃, —CH₂CH₃, —CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃,—OCH₂CH₂OH, —OCH₂CH₂OCH₃, —F, —Cl, —Br and —CN.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein X is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is (C₁-C₆)alkyl optionallysubstituted with one, two, three, four or five substitutentsindependently selected for each occurrence from the group consisting of—F, —Cl, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is unsubstituted (C₁-C₆)alkyl. Incertain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is unsubstituted branched(C₁-C₆)alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is (C₁-C₃)alkyl optionallysubstituted with one, two, three, four or five substitutentsindependently selected for each occurrence from the group consisting of—F, —Cl, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is methyl optionally substitutedwith one, two or three substitutents independently selected for eachoccurrence from the group consisting of —F, —Cl, —Br, —OH, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is ethyl optionally substitutedwith one, two, three, four or five substitutents independently selectedfor each occurrence from the group consisting of —F, —Cl, —Br, —OH,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is n-propyl optionally substitutedwith one, two, three, four or five substitutents independently selectedfor each occurrence from the group consisting of —F, —Cl, —Br, —OH,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is i-propyl optionally substitutedwith one, two, three, four or five substitutents independently selectedfor each occurrence from the group consisting of —F, —Cl, —Br, —OH,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is methyl substituted with(C₃-C₆)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is ethyl substituted with —CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is ethyl substituted with —OH and—CF₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is ethyl substituted withcycoalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is (C₃-C₁₀)cycloalkyl optionallysubstituted with one, two, three, four or five substitutentsindependently selected for each occurrence from the group consisting of—F, —CI, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is unsubstituted(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is cyclopropyl optionallysubstituted with one, two, three or four substitutents independentlyselected for each occurrence from the group consisting of —F, —Cl, —Br,—OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is cyclobutyl optionallysubstituted with one, two, three, four or five substitutentsindependently selected for each occurrence from the group consisting of—F, —Cl, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is cyclopentyl optionallysubstituted with one, two, three, four or five substitutentsindependently selected for each occurrence from the group consisting of—F, —Cl, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is cyclohexyl optionallysubstituted with one, two, three, four or five substitutentsindependently selected for each occurrence from the group consisting of—F, —Cl, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is cycloheptyl optionallysubstituted with one, two, three, four or five substitutentsindependently selected for each occurrence from the group consisting of—F, —Cl, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is cyclooctyl optionallysubstituted with one, two, three, four or five substitutentsindependently selected for each occurrence from the group consisting of—F, —Cl, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is phenyl optionally substitutedwith one, two, three, four or five substitutents independently selectedfor each occurrence from the group consisting of —F, —Cl, —Br, —OH,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is phenyl optionally substitutedwith one, two, three, four or five substitutents independently selectedfor each occurrence from the group consisting of —F, —Cl, —Br, —OH and—CH₃.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is indanyl optionally substitutedwith one, two, three, four or five substitutents independently selectedfor each occurrence from the group consisting of —F, —Cl, —Br, —OH,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is unsubstituted indanyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is tetrahydrothiophenyl optionallysubstituted with one, two, three, four or five substitutentsindependently selected for each occurrence from the group consisting of—F, —Cl, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl and(C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is unsubstitutedtetrahydrothiophenyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is thietanyl optionally substitutedwith one, two, three, four or five substitutents independently selectedfor each occurrence from the group consisting of —F, —Cl, —Br, —OH,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is unsubstituted thietanyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is.

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

In certain embodiments, the present invention relates to any of theaforementioned compounds, wherein R² is

Another embodiment of the invention is a compound selected from thegroup consisting of the compounds of Examples 1-100, 109-113 andpharmaceutically acceptable salts thereof.

Therapeutic Applications

It is contemplated that the compounds of Formula I provide therapeuticbenefits to subjects suffering from an immune disorder or inflammatorydisorder. Accordingly, one aspect of the invention provides a method oftreating a disorder selected from the group consisting of an immunedisorder or inflammatory disorder. The method comprises administering atherapeutically effective amount of a compound of Formula I to a subjectin need thereof to ameliorate a symptom of the disorder, wherein FormulaI are as described above. In certain embodiments, the particularcompound of Formula I is a compound defined by one of the embodimentsdescribed above.

In certain embodiments, the disorder is an immune disorder. In certainother embodiments, the disorder is an inflammatory disorder. In certainother embodiments, the disorder is an autoimmune disorder. In certainother embodiments, the disorder is rheumatoid arthritis, psoriasis,chronic graft-versus-host disease, acute graft-versus-host disease,Crohn's disease, inflammatory bowel disease, multiple sclerosis,systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenicthrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma,ulcerative colitis, asthma, or epidermal hyperplasia.

In certain other embodiments, the disorder is cartilage inflammation,bone degradation, arthritis, juvenile arthritis, juvenile rheumatoidarthritis, pauciarticular juvenile rheumatoid arthritis, polyarticularjuvenile rheumatoid arthritis, systemic onset juvenile rheumatoidarthritis, juvenile ankylosing spondylitis, juvenile enteropathicarthritis, juvenile reactive arthritis, juvenile Reter's Syndrome, SEASyndrome, juvenile dermatomyositis, juvenile psoriatic arthritis,juvenile scleroderma, juvenile systemic lupus erythematosus, juvenilevasculitis, pauciarticular rheumatoid arthritis, polyarticularrheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosingspondylitis, enteropathic arthritis, reactive arthritis, Reter'sSyndrome, dermatomyositis, psoriatic arthritis, vasculitis, myositis,polymyositis, osteoarthritis, polyarteritis nodossa, Wegener'sgranulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis,sclerosis, primary biliary sclerosis, sclerosing cholangitis,dermatitis, atopic dermatitis, atherosclerosis, Still's disease, chronicobstructive pulmonary disease, Guillain-Barre disease, Type I diabetesmellitus, Graves' disease, Addison's disease, Raynaud's phenomenon,autoimmune hepatitis, psoriatic epidermal hyperplasia, plaque psoriasis,guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermicpsoriasis, giant cell arteritis, nonalcoholic hepatic steatosis, or animmune disorder associated with or arising from activity of pathogeniclymphocytes.

In certain embodiments, the psoriasis is plaque psoriasis, guttatepsoriasis, inverse psoriasis, pustular psoriasis, or erythrodermicpsoriasis.

In certain other embodiments, the disorder is noninfectious uveitis,Behcet's disease or Vogt-Koyanagi-Harada syndrome.

Another aspect of the invention provides for the use of a compound ofFormula I in the manufacture of a medicament. In certain embodiments,the medicament is for treating a disorder described herein.

Another aspect of the invention provides for the use of a compound ofFormula I for treating a medical disorder, such a medical disorderdescribed herein.

Further, it is contemplated that compounds of Formula I can inhibit theactivity of RORγ. Accordingly, another aspect of the invention providesa method of inhibiting the activity of RORγ. The method comprisesexposing a RORγ to an effective amount of a compound of Formula I toinhibit said RORγ, wherein Formula I is as described above. In certainembodiments, the particular compounds of Formula I are the compounddefined by one of the embodiments described herein.

Further, it is contemplated that compounds of Formula I can reduce theamount of interleukin-17 (IL-17) in a subject. IL-17 is a cytokine thataffects numerous biological functions, including inducing and mediatingpro-inflammatory responses. Accordingly, another aspect of the inventionprovides a method of reducing the amount of IL-17 in a subject. Themethod comprises administering to a subject an effective amount of acompound of I to reduce the amount of IL-17 in the subject, whereinFormula I is as described above. In certain embodiments, the particularcompounds of Formula I are the compounds defined by one of theembodiments described herein.

In certain embodiments, the subject is a human. In certain embodiments,administering the compound reduces the amount of IL-17 produced by Th-17cells in the subject. A change in the amount of IL-17 produced by, forexample, Th-17 cells can be measured using procedures described in theliterature, such as an ELISA assay or intracellular staining assay.

Further, it is contemplated that compounds of Formula I may inhibit thesynthesis of IL-17 in a subject. Accordingly, another aspect of theinvention provides a method of inhibiting the synthesis IL-17 in asubject. The method comprises administering to a subject an effectiveamount of a compound of Formula I to inhibit the synthesis IL-17 in thesubject, wherein Formula I is as described above. In certainembodiments, the particular compounds of Formula I are the compoundsdefined by one of the embodiments described herein.

The description above describes multiple embodiments providingdefinitions for variables used herein. The application specificallycontemplates all combinations of such variables.

Combination Therapy

Another aspect of the invention provides for combination therapy. Forexample, the compounds of Formula I or their pharmaceutically acceptablesalts may be used in combination with additional therapeutic agents totreat medical disorders, such as medical disorders associated withinappropriate IL-17 pathway activity. Exemplary additional therapeuticagents include, for example, (1) a TNF-α inhibitor; (2) a non-selectiveCOX-I/COX-2 inhibitor; (3) a selective COX-2 inhibitor, such ascelecoxib and rofecoxib; (4) other agents for treating inflammatorydisease and autoimmune disease including, for example, methotrexate,leflunomide, sulfasalazine, azathioprine, penicillamine, bucillamine,actarit, mizoribine, lobenzarit, hydroxychloroquine, d-penicillamine,aurothiomalate, auranofin, parenteral gold, oral gold, cyclophosphamide,Lymphostat-B, a BAFF/APRIL inhibitor, CTLA-4-Ig, or a mimetic ofCTLA-4-Ig; (5) a leukotriene biosynthesis inhibitor, such as a5-lipoxygenase (5-LO) inhibitor, or a 5-lipoxygenase activating protein(FLAP) antagonist; (6) a LTD4 receptor antagonist; (7) aphosphodiesterase type IV (PDE-IV) inhibitor, such as cilomilast(ariflo) or roflumilast; (8) an antihistamine HI receptor antagonist;(9) an od- and oc2-adrenoceptor agonist; (10) an anticholinergic agent;(11) a β-adrenoceptor agonist; (12) an insulin-like growth factor type I(IGF-1) mimetic; (13) a glucocorticosoid; (14) a kinase inhibitor suchas an inhibitor of a Janus Kinase (e.g., JAK 1 and/or JAK2 and/or JAK 3and/or TYK2), p38 MAPK, Syk or IKK2; (15) a B-cell target biologic suchas rituximab; (16) a selective co-stimulation modulator such asabatacept; (17) an interleukin inhibitor or interleukin receptorinhibitor, such as the IL-1 inhibitor anakinra, IL-6 inhibitortocilizumab, and IL12/IL-23 inhibitor ustekimumab; (18) an anti-IL17antibody, anti-IL21 antibody, or anti-IL22 antibody (19) a S1P1 agonist,such as fingolimod; (20) an interferon, such as interferon beta 1; (21)an integrin inhibitor such as natalizumab; (22) a mTOR inhibitor such asrapamycin, cyclosporin and tacrolimus; (23) a non-steroidalantiinflammatory agent (NSAID), such as propionic acid derivatives(alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen,fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen,miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,tiaprofenic acid, and tioxaprofen), acetic acid derivatives(indomethacin, acemetacin, alclofenac, clidanac, diclofenac,fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac,oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac),fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamicacid, niflumic acid and tolfenamic acid), biphenylcarboxylic acidderivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam,sudoxicam and tenoxican), salicylates (acetyl salicylic acid,sulfasalazine) and pyrazolones (apazone, bezpiperylon, feprazone,mofebutazone, oxyphenbutazone, phenylbutazone); (24) a NRF2 pathwayactivator, such as the fumaric acid derivative, BG-12; and (25) achemokine or chemokine receptor inhibitor, such as a CCR9 antagonist.

In certain embodiments, the additional therapeutic agent is selectedfrom the group consisting of corticosteroids, vitamin D3, anthralin andretinoids. In certain embodiments, the additional therapeutic agent is acorticosteroid. In certain embodiments, the additional therapeutic agentis vitamin D3. In certain embodiments, the additional therapeutic agentis anthralin. In certain embodiments, the additional therapeutic agentis a retinoid.

The amount of the compounds of Formula I and additional therapeuticagent and the relative timing of administration may be selected in orderto achieve a desired combined therapeutic effect. For example, whenadministering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like.Further, for example, a compound of Formula I may be administered duringa time when the additional therapeutic agent(s) exerts its prophylacticor therapeutic effect, or vice versa.

The doses and dosage regimen of the active ingredients used in thecombination therapy may be determined by an attending clinician. Incertain embodiments, the compound of Formula I and the additionaltherapeutic agent(s) are administered in doses commonly employed whensuch agents are used as monotherapy for treating the disorder. In otherembodiments, the compound of Formula I and the additional therapeuticagent(s) are administered in doses lower than the doses commonlyemployed when such agents are used as monotherapy for treating thedisorder. In certain embodiments, a compound of Formula I and theadditional therapeutic agent(s) are present in the same composition,which is suitable for oral administration.

In certain embodiments, the compound of Formula I and the additionaltherapeutic agent(s) may act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of a compound of Formula I, a pharmaceuticallyacceptable carrier, vehicle or diluent, and optionally at least oneadditional therapeutic agent listed above.

Pharmaceutical Compositions and Dosing Considerations

Typically, a compound of the invention is administered in an amounteffective to treat a condition as described herein. The compounds of theinvention are administered by any suitable route in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. Therapeutically effective doses ofthe compounds required to treat the progress of the medical conditionare readily ascertained by one of ordinary skill in the art usingpreclinical and clinical approaches familiar to the medicinal arts. Theterm “therapeutically effective amount” as used herein refers to thatamount of the compound being administered which will relieve to someextent one or more of the symptoms of the disorder being treated.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. The term “treating” alsoincludes adjuvant and neo-adjuvant treatment of a subject.

As indicated above, the invention provides pharmaceutical compositions,which comprise a therapeutically-effective amount of one or more of thecompounds described above, formulated together with one or morepharmaceutically acceptable carriers (additives) and/or diluents. Thepharmaceutical compositions may be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: (1) oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets, e.g., those targeted forbuccal, sublingual, and systemic absorption, boluses, powders, granules,pastes for application to the tongue; (2) parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)nasally.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The invention also includes pharmaceutical compositions utilizing one ormore of the present compounds along with one or more pharmaceuticallyacceptable carriers, excipients, vehicles, etc.

Topical formulations of the presently disclosed compounds may beadministered topically, (intra)dermally, or transdermally to the skin ormucosa. Topical administration using such preparations encompasses allconventional methods of administration across the surface of the bodyand the inner linings of body passages including epithelial and mucosaltissues, including transdermal, epidermal, buccal, pulmonary,ophthalmic, intranasal, vaginal and rectal modes of administration.Typical formulations for this purpose include gels, hydrogels, lotions,solutions, creams, colloid, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibres, bandagesand microemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Such topicalformulations may be prepared in combination with additionalpharmaceutically acceptable excipients.

In certain embodiments, a penetration enhancer may be used. Examples ofpenetration enhancers include, for example, saturated C10-C18 fattyalcohols (such as decyl alcohol, lauryl alcohol, myristyl alcohol, cetylalcohol and stearyl alcohol), cis-unsaturated C10-C18 fatty alcohols(such as oleyl alcohol, linoleyl alcohol, γ-linolenyl alcohol andlinolenyl alcohol), C10-C18 fatty acids (which when saturated mayinclude capric acid, lauric acid, myristic acid, palmitic acid, stearicacid and arachidic acid), cis-unsaturated fatty acids (such aspalmitoleic acid (cis-9-hexadecenoic acid), oleic acid(cis-9-octadecenoic acid), cis-vaccenic acid (cis-11-octadecenoic acid),linoleic acid (cis-9,12-octadecadienoic acid), γ-linolenic acid(cis-6,9,12-octadecatrienoic acid), linolenic acid(cis-9,12,15-octadecatrienoic acid) and arachidonic acid(cis-5,8,11,14-eicosatetraenoic acid)). In certain embodiments, thepenetration enhancers may be used amounts ranging from about 0.1 toabout 5% (w/v).

In certain embodiments, topical formulations which contain one or morecompounds of the invention in therapeutically effective amounts that maybe given in daily or twice daily doses to patients in need.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof. Other excipients which enhancethe stability of the formulations include aldehyde scavengers, such asglycerine and propylene glycol, and antioxidants, such as butylhydroxyanisole (BHA), butyl hydroxytoluene (BHT), propyl gallate,ascorbic acid (Vitamin C), polyphenols, tocopherols (Vitamin E), andtheir derivatives.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of this invention is dissolvedor suspended in a suitable carrier. A typical formulation suitable forocular or aural administration may be in the form of drops of amicronised suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (i.e., absorbable gel sponges,collagen) and non-biodegradable (i.e., silicone) implants, wafers,lenses and particulate or vesicular systems, such as niosomes orliposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose,or a heteropolysaccharide polymer, for example, gelan gum, may beincorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone; as amixture, for example, in a dry blend with lactose; or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly (anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Preferably, the compounds areadministered at about 0.01 mg/kg to about 200 mg/kg, more preferably atabout 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5mg/kg to about 50 mg/kg.

When the compounds described herein are co-administered with anotheragent (e.g., as sensitizing agents), the effective amount may be lessthan when the agent is used alone.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain embodiments, preferreddosing is one administration per day.

The invention further provides a unit dosage form (such as a tablet orcapsule) comprising a compound of Formula I or a specific compounddescribed herein, or pharmaceutically acceptable salts thereof, in atherapeutically effective amount for the treatment of an immune orinflammatory disorder, such as one of the particular immune disorders orinflammatory disorders described herein.

General Synthetic Schemes and Procedures

The compounds of Formula I may be prepared by the methods describedbelow, together with synthetic methods known in the art of organicchemistry, or modifications and derivatizations that are familiar tothose of ordinary skill in the art. The starting materials used hereinare commercially available or may be prepared by routine methods knownin the art (such as those methods disclosed in standard reference bookssuch as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI(published by Wiley-Interscience)). Preferred methods include, but arenot limited to, those described below.

During any of the following synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene, ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Chemistry, John Wiley & Sons, 1999, which are herebyincorporated by reference.

Compounds of Formula I or their pharmaceutically acceptable salts, canbe prepared according to the reaction Schemes discussed herein below.Unless otherwise indicated, the substituents in the Schemes are definedas above. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

It will be understood by one skilled in the art that the varioussymbols, superscripts and subscripts used in the schemes, methods andexamples are used for convenience of representation and/or to reflectthe order in which they are introduced in the schemes, and are notintended to necessarily correspond to the symbols, superscripts orsubscripts in the appended claims. The schemes are representative ofmethods useful in synthesizing the compounds of the present invention.They are not to constrain the scope of the invention in any way.

Compounds of Formula I may be prepared as single enantiomer or as amixture of individual enantiomers which includes racemic mixtures.Methods to obtain preferentially a single enantiomer from a mixture ofindividual enantiomers or a racemic mixture are well known to thoseordinarily skilled in the art of organic chemistry. Such methods includebut are not limited to preferential crystallization of diastereomericsalts (e.g. tartrate or camphor sulfonate), covalent derivatization by achiral, non-racemic reagent followed by separation of the resultingdiastereomers by common methods (e.g. crystallization, chromatographicseparation, or distillation) and chemical reversion to scalemiccompound, Simulated Moving Bed technology, or high/medium-pressureliquid chromatography or supercritical fluid chromatography employing achiral stationary phase. These techniques may be performed on the finalcompounds of the invention or on any intermediates to compounds of theinvention which bear a stereogenic center. Also, to facilitateseparation by any of the methods described above, the compounds of theinvention or any intermediates to the compounds of the invention whichbear a stereogenic center may be transiently reacted with an achiralreagent, separated, and then reverted to scalemic compound by standardsynthetic techniques.

Compounds of Formula (I) may be prepared as described in Scheme A.Cross-coupling of aryl halides A-1 (prepared as described in SchemesB-C) with vinyl boronates (prepared as described in Scheme D) or vinylboronic acids affords compounds of the Formula A-2. Subsequent reductionof the nitro group and the olefin furnished compounds of Formula A-3.The resulting amine A-3 may be transformed to amides by the reactionwith acid chlorides in the presence of base or carboxylic acids withappropriate coupling agents to afford compounds of Formula A-4.

The intermediate of Formula A-1 employed in Scheme A where Y istrifluoromethyl is prepared as described in Scheme B. Transhalogenationof 4-chloro-1H-pyrrolo[2,3-b]pyridine (B−1) employing sodium iodidefollowed by sulfonylation of the resulting iodide B-2 withphenylsulfonyl chloride and base provides compound B-3. Nitration of B-3with a tetraalkylammonium salt affords compound B-4 which is thensubjected to copper-mediated trifluromethylation to provide compoundB-5. Alkylation of the indole nitrogen by iodomethane or iodoethane inthe presence of an inorganic base provides compounds of the Formula A-1(Y=trifluoromethyl).

The intermediate of Formula A-1 employed in Scheme A where Y is methylis prepared as described in Scheme C. Nitration of C-1 provides compoundC-2 which is then converted to C-3 by the treatment withtrimethylaluminum in the presence of a palladium catalyst. Deprotectionof the indole nitrogen followed by iodination provided compound C-5.Alkylation of the indole nitrogen by iodomethane or iodoethane in thepresence of an inorganic base provides compounds of the Formula A-1(Y=methyl).

The intermediate of Formula D-3 employed in Scheme A is prepared asdescribed in Scheme D. Acid-mediated removal of the carbamatefunctionality found in D-1 followed by acylation of the resulting aminewith acid chlorides (R²COCl) or carboxylic acids (R²CO₂H) providescompounds of the Formula D-3.

Alternatively, compounds of Formula (I) may be prepared as described inScheme E. Cross-coupling of aryl halides A-1 (prepared as described inSchemes B-C) with vinyl boronate D-1 followed by reduction of the nitrogroup and the olefin furnished compounds of the Formula E-2. Subsequentbenzoylation of the resulting amine followed by acid-mediated removal ofthe carbamate functionality provides compounds of the Formula E-4.Acylation of the resulting amine E-4 with acid chlorides (R²COCl) orcarboxylic acids (R²CO₂H) provides compounds of the Formula E-5.

Alternatively, compounds of Formula (I) may be prepared as described inScheme F. Compounds of the Formula E-1 (prepared as described in SchemeE) are treated with acid to afford the corresponding amines F-1. Theresulting amine is then reacted with an acid chlorides (R²COCl) in thepresence of a base or a carboxylic acids (R²CO₂H) in the presence ofsuitable coupling agent to provide compounds of the Formula A-2 whichmay be further transformed as described in Scheme A.

Carboxylic acids of the Formula R²CO₂H employed in Scheme D-E andsubsequent Schemes may be commercially available, prepared by proceduresdescribed in the literature, or prepared as described in Scheme G.Examples of R²CO₂H prepared by literature procedures include thefollowing: (3ar,7ac)-hexahydro-indan-2ξ-carboxylic acid (Granger, R., etal, Bull. Soc. Chim. Fr. 1968, 1445-50.); 3,3,4-trimethyl-pentanoic acid(Beckwith, A., et al, Australian J. Chem. 1977, 30, 2733-39.); and(1S,2R,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid (Evans, D. A. et al,J. Am. Chem. Soc. 1988, 110, 1238.). (R)-2,3,3-Trimethylbutanoic acidand (S)-2,3,3-trimethylbutanoic acid may be prepared as described byKido, M. et al Tetrahedron: Asym. 2007, 18, 1934-1947; and thietane acid(see WO2013/7582, which is hereby incorporated by reference for thepreparation of thietane acid). The following acids were prepared usingprocedures which are described in this application:(R)-2-(bicyclo[1.1.1]pentan-1-yl)propanoic acid,(S)-2-(bicyclo[1.1.1]pentan-1-yl)propanoic acid,(R)-2-cyclopentylpropanoic acid, and (S)-2-cyclopentylpropanoic acid.Specific examples of R₂CO₂H according to the Formula G-4 can be preparedfrom acids G-1 where R may be alkyl, cycloalkyl or aryl which arereacted with an optically active chiral oxazolidinone (e.g. (R)-benzyloxazolidinone, (R)-4-Isopropyl-2-oxazolidinone) to provide compounds ofthe Formula G-2. Base mediated alkylation and subsequent removal of theoxazolidinone auxiliary furnishes acids of the Formula G-4 in highoptical purity. By employing a chiral oxazolidinone of a differentabsolute configuration (e.g. (S)-benzyl oxazolidinone,(S)-4-Isopropyl-2-oxazolidinone), chiral acids G-4 of bothconfigurations can be obtained.

Alternatively, compounds of Formula (I) may be prepared as described inScheme H where R may be one or more methyl substituents or a bridgedethynyl radical. Aryl halides of the Formula A-1 (prepared as describedin Schemes B-C) are converted to the corresponding boronates throughcatalytic methods involving palladium. Cross-coupling of the resultingboronate H-1 with vinyl triflates (prepared as described in SchemesI-N,S) followed by reduction of the nitro group and the olefin affordscompounds of the Formula H-4. Subsequent benzoylation of the resultingamine followed by acid-mediated removal of the carbamate functionalityprovides H-6. Acylation of the resulting amine H-6 with acid chlorides(R²COCl) or carboxylic acids (R²CO₂H) provides compounds of the FormulaH-7.

Triflates of the Formula H-2 employed in Scheme H being substitutedtwice by methyl at the 2-position of the piperidine ring may be preparedas described in Scheme I. Treatment of the ketone I-1 with base followedby quench with a triflating reagent (e.g. phenyl triflimide) providescompound H-2A.

Triflates of the Formula H-2 employed in Scheme H being substituted bymethyl at the 3-position of the piperidine ring may be prepared asdescribed in Scheme J. Hydrogenolysis of J-1 affords the correspondingamine J-2 which is then treated with base and reagents capable ofgenerating t-butyl carbamates (e.g. di-tert-butyl dicarbonate) toprovide J-3. Treatment of the resulting ketone J-3 with base followed byquench with a triflating reagent (e.g. phenyl triflimide) providescompound H-2B.

Triflates of the Formula H-2 employed in Scheme H being substituted byan ethynyl radical connecting both 2-positions of the piperidine ringmay be prepared as described in Scheme K. Condensation of compounds K-1and K-2 in the presence of base affords compound K-3. Diester K-3undergoes cyclization in the presence of base (e.g. potassiumtert-butoxide) to provide K-4 which upon heating results in compoundK-5. Carbamoylation of the resulting amine K-5 provides compound K-6.Treatment of the resulting ketone K-6 with base followed by quench witha triflating reagent (e.g. phenyl triflimide) provides compound H-2C.

Triflates of the Formula H-2 employed in Scheme H being substituted bymethyl at the 2-position and the 6-position of the piperidine ring maybe prepared as described in Scheme L. Treatment of the ketone L-1 withbase followed by quench with a triflating reagent (e.g. phenyltriflimide) provides compound H-2D.

Triflates of the Formula H-2 employed in Scheme H being substituted bymethyl at the 2-position and the 5-position of the piperidine ring maybe prepared as described in Scheme M. Treatment of the ketone M-1 withbase followed by quench with a triflating reagent (e.g. phenyltriflimide) provides compound H-2E.

Triflates of the Formula H-2 employed in Scheme H being substituted bymethyl at the 3-position and the 5-position of the piperidine ring maybe prepared as described in Scheme N. Ketone N-1 is deprotonated with astrong base and then subsequently reacted with an alkyl halide (e.g.methyl iodide) to provide N-2. Hydrogenolysis of N-2 with hydrogen and apalladium catalyst in the presence of a carbamoylating reagent (e.g.di-tert-butyl dicarbonate) affords N-3. Treatment of the resultingketone N-3 with base followed by quenching with a triflating reagent(e.g. phenyl triflimide) provides compound H-2F.

Alternatively, compounds of Formula (I) where the piperidine issubstituted by methyl at the 2-position may be prepared as described inScheme O. Hydrogenolysis of O-1 followed by acylation of the resultingamine O-2 with acid chlorides (R₂COCl) or carboxylic acids (R₂CO₂H)affords compounds of the Formula O-3. Treatment of the resulting ketoneO-3 with base followed by quench with a triflating reagent (e.g. phenyltriflimide) provides compound O-4. Cross-coupling of O-4 with arylboronates of the Formula H-1 provides compounds of the Formula O-5 whichare converted to O-6 after reduction of the nitro group and olefin.Subsequent benzoylation provides compounds of the Formula O-8. Thismethod of preparation may also be applied to the opposite enantiomerrelative to what is exemplified.

Compounds of Formula (I) may be prepared as described in Scheme P.Metallation of iodopyridine P-1 followed by conjugate addition of theresulting anion with the nitroalkene P-2 (prepared as described inScheme Q) provides the substituted pyridine P-3. Removal of thecarbamate group through treatment with acid followed by reaction of theresulting amine with carboxylic acids (R²CO₂H) or carboxylic acidchlorides (R²COCl) under amide bond-forming conditions providescompounds of the Formula P-5. Reduction of the nitro group followed bytreatment with either acidic or basic conditions facilitates cyclizationto form 2,3-dihydro-7-azaindoles P-6. Treatment of P-6 with methyliodide and base affords compounds P-7. Treatment of P-7 withtetraalkylammonium salts results in nitration at the 5-position andaromatization of the ring system. Reduction of the nitro group andsubsequent benzoylation through amide bond formation conditions providescompounds of the Formula P-10.

Compounds P-2 employed in Scheme P may be prepared as described inScheme Q. The commercially available bicyclic ketone was first convertedto the carbamate-protected derivative Q-2 by reduction of the benzylgroup in the presence of the appropriate carbamic anhydride. Next,homologation of the ketone through the use of phosphonium salts and basefurnishes methyl vinyl ether Q-3 which upon treatment with acid providesthe corresponding aldehyde Q-4. Treatment of Q-4 with nitromethane inthe presence of base followed by elimination of water from the resultingnitroalcohol Q-5 provides nitroalkene P-2.

Compounds of Formula (I) may be prepared as exemplified by the syntheticroute described in Scheme R. Lithiation of dihalopyridine R-1 followedby addition to nitroolefin P-2, prepared as described in Scheme P,results in the 1,4-addition product R-2. The amine protecting group isremoved in the presence of acid (e.g. HCl) to afford compound R-3 as acorresponding salt form of the acid used. Condensation of R-3 with anappropriate acid chloride (R²COCl) or activated carboxylic acid (R²CO₂H)affords compounds of the Formula R-4. A zinc-mediated reductivecyclization reaction on R-4 provides dihydropyrrolopyridines of theFormula R-5. Methylation of R-5 using iodomethane and sodium hydridefollowed by nitration-oxidation using tetramethylammonium nitrateaffords compounds of the Formula R-7. Zinc-mediated methylation of R-7provides 4-methylpyrrolopyridines of the Formula R-8. Reduction of thenitro group, followed by acylation with an appropriate benzoyl chloride(XCOCl) or activated benzoic acid (XCO₂H) furnishes compounds of theFormula R-9.

Triflates of the Formula H-2 employed in Scheme H being bridged by anethylene (—CH₂CH₂—) group between the 2- and 6-positions of thepiperidine ring may be prepared as described in Scheme S. Treatment ofthe ketone S-1 with base followed by quench with a triflating reagent(e.g. phenyl triflimide) provides compound H-2G.

EXEMPLIFICATION

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.The following illustrate the synthesis of various compounds of thepresent invention. Additional compounds within the scope of thisinvention may be prepared using the methods illustrated in theseExamples, either alone or in combination with techniques generally knownin the art.

Experiments were generally carried out under inert atmosphere (nitrogenor argon), particularly in cases where oxygen- or moisture-sensitivereagents or intermediates were employed. Commercial solvents andreagents were generally used without further purification, includinganhydrous solvents where appropriate. Mass spectrometry data is reportedfrom either liquid chromatography-mass spectrometry (LCMS), atmosphericpressure chemical ionization (APCI) or gas chromatography-massspectrometry (GCMS) instrumentation. Chemical shifts for nuclearmagnetic resonance (NMR) data are expressed in parts per million (ppm,δ) referenced to residual peaks from the deuterated solvents employed.Coupling constants (J values) are reported in Hertz.

Chiral purity of scalemic compounds was determined by chiral SFC(super-critical fluid chromatography) employing one of the followingconditions: Method A: Chiralpak AD-3 150×4.6 mm ID, 3 μm, IPA/CO₂ (0.05%DEA), 5-40%, 2.5 mL/min, 10 min; Method B: Chiralpak AS-H 150×4.6 mm ID,5 μm, MeOH/CO₂ (0.05% DEA), 5-40%, 3 mL/min, 10 min; Method C: ChiralCelOJ-H 250×4.6 mm ID, 5 μm, IPA/CO₂ (0.05% DEA), 5-40%, 2.35 mL/min, 10min; Method D: Lux Cellulose-1 250 mm×4.6 mm ID, 5 μm, MeOH/CO₂ (0.2%NH₄ ⁺), 5-60%, 3 mL/min, 10 min; Method E: ChiralPak AD-3 50×4.6 mm ID,3 μm, IPA/CO₂ (0.05% DEA), 5-40%, 2.5 mL/min, 10 min; Method F:ChiralCel OD-3 150×4.6 mm ID, 3 μm, IPA/CO₂ (0.05% DEA) 40%, 2.5 mL/min;Method G: ChiralCel OJ-H 100×4.6 mm ID, 5 μm, Ethanol/CO₂ (0.05% DEA),5-20%, 2.35 mL/min, 20 min; Method H: Chiralcel OJ-3 50×4.6 mm, 3 μm,MeOH/CO₂ (0.05% DEA), 5-40%, 4 mL/min, 3 min; Method I: Chiralpak AD-350×4.6 mm, 3 μm, EtOH/CO₂ (0.05% DEA), 5-40%, 4 mL/min, 3 min; Method J:Chiralcel OD-H 4.6×100 mm, 5 μm, EtOH/CO₂ (0.2% NH₄ ⁺), 40-60%, 1.5mL/min, 5 min; Method K: Chiralcel OJ-3 50×4.6 mm, 3 μm, MeOH/CO₂ (0.05%DEA), 5-40%, 4 mL/min, 10 min; Method L: DIKMA Diamonsil(2) C18 200×20mm, 5 μm, MeCN/H₂O, 35 ml/min, 10 min; Method M: Chiralpak AD-3 50×4.6mm ID, 3 μm, EtOH/CO₂ (0.05% DEA), 5-40%, 4.0 mL/min, 2.5 min; Method N:Chiralpak AS-3 100×4.6 mm, 3 μm, MeOH/CO₂ (0.05% DEA), 5-40%, 2.8mL/min, 8 min; Method O: Chiralcel OJ-2 50×3.0 mm, 5 μm, EtOH/CO₂ (0.2%NH₄ ⁺), 5-40%, 6 mL/min, 10 min; Method P: Ultimate XB-C18 50×3.0 mm, 3μm, MeCN/H₂O, 35 mL/min, 5 min; Method Q: Chiralpak AD-H 250×4.6 mm ID,5 μm, EtOH/CO₂ (0.05% DEA), 5-40%, 2.5 mL/min, 10 min; Method R:Chiralpak AD-3 50×4.6 mm ID, 3 μm, MeOH/CO₂ (0.05% DEA), 5-40%, 4.0mL/min, 7.5 min; Method S: ChiralCel OJ-H 250×30 mm ID, 5 μm, EtOH/CO₂(0.05% DEA), 20%, 60 mL/min, 10 min; Method T: Chiralpak AS-H 100×4.6 mmID, 5 μm, MeCN/MeOH/CO₂ (0.05% DEA), 15/15/70, 1.5 mL/min, 10 min;Method U: Chiralpak AS-H 150×4.6 mm ID, 5 μm, MeOH/CO₂ (0.05% DEA),5-40%, 3 mL/min, 8 min; Method V: Chiralpak AS-H 250×4.6 mm ID, 5 μm,EtOH/CO₂ (0.05% DEA), 5-40%, 2.35 mL/min, 10 min; Method W: ChiralcelOJ-3 50×4.6 mm ID, 3 μm, EtOH/CO₂ (0.05% DEA), 5-40%, 4 mL/min, 10 min;Method X: Chiralcel OJ-H, 250×4.6 mm, ID, 5 μm, MeOH/CO₂ (0.05% DEA),5-40%, 2.35 mL/min, 10 min; Method Y: Chiralpak AD-3, 50×4.6 mm, ID, 3μm, EtOH/CO₂ (0.05% DEA), 5-40%, 4 mL/min, 10 min; Method Z: ChiralpakAS-H, 100×4.6 mm, ID, 5 μm, ACN/MeOH (50/50)/CO₂, 1.5 mL/min, 10 min;Method AA: ChiralCel IA, 100×4.6 mm, 5 μm, CO₂/MeOH, 60/40, 1.5 mL/min,10 min. Method AB: Ultimate XB-C18, 3 μm, 50×3 mm, MeCN/H₂O (0.1% TFA),1-100%, 1.5 mL/min, 10 min; Method AC: Chiral Tech OD-H, 5 μm, 250×4.6mm, CO₂/MeOH, 5-40%, 3.0 mL/min, 10 min.

For syntheses referencing procedures in other Examples, reactionconditions (length of reaction and temperature) may vary. In general,reactions were followed by thin layer chromatography or massspectrometry, and subjected to work-up when appropriate. Purificationsmay vary between experiments: in general, solvents and the solventratios used for eluants/gradients were chosen to provide appropriateRf's or retention times (RetT).

The chemical names for the compounds of the invention described belowwere generated using CambridgeSoft's ChemBioDraw Ultra version 13.0.2(CambridgeSoft Corp., Cambridge Mass.).

The following abbreviations are used herein: DCM: dichloromethane; DEA:diethylamine; DIPEA: diisopropylethylamine; DME: 1,2-dimethoxyethane;DMF: dimethylformamide; EtOAc: ethyl acetate; EtOH: ethanol; HATU:1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate; MeOH: methanol; MTBE: methyl t-butyl ether;PE: petroleum ether; TEA: triethylamine; and THF: tetrahydrofuran.

Example 1 Preparation of3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide

Step 1: 4-iodo-1H-pyrrolo[2,3-b]pyridine. This reaction was carried outin three parallel batches. To a solution of4-chloro-1H-pyrrolo[2,3-b]pyridine (500 g, 3.28 mol) in acetonitrile (20L) was added NaI (2950 g, 19.66 mol) at room temperature. Then acetylchloride (1030 g, 13.11 mol) was added dropwise to the reaction mixtureat room temperature. The reaction mixture was stirred at 100° C. for 60hr. The reaction mixture was cooled to room temperature and neutralizedwith aqueous NaHCO₃ to pH=7. The mixture was stirred for 30 min. Thereaction mixtures from three batches were concentrated. NaHSO₃(saturated, 1 L) was added to the reaction mixture. The mixture wasstirred for 20 min and extracted with DCM (20 L×3). The combined organiclayer was concentrated to give crude product. To a solution of the crudeproduct in MeOH (20 L) was added NaOH (2 M, 10 L) at room temperature.The reaction mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with DCM (20 L×3). The combined organiclayers were washed with brine (10 L), dried over Na₂SO₄, filtered andconcentrated to give the title compound (1500 g, 93.7% combined yield)as a yellow solid. The material was used for the next step withoutfurther purification. ¹H NMR (CDCl₃) δ 10.44 (br s, 1H), 7.96 (d, J=5.2Hz, 1H), 7.53 (d, J=4.8 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 6.43 (d, J=2.8Hz, 1H).

Step 2: 4-Iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. Thisreaction was carried out in three parallel batches. To a solution ofNaOH (344 g, 8.61 mol) in DCM (16 L) was added tetrabutylammoniumsulphate (48.7 g, 143.4 mmol) at 0° C. Then4-iodo-1H-pyrrolo[2,3-b]pyridine (700 g, 2.87 mol) was added to thereaction mixture at 0° C. The reaction mixture was stirred at 0° C. for10 min. Phenyl sulphonyl chloride (760 g, 4.30 mol) was added dropwiseto the reaction mixture at 0° C. After addition, the reaction mixturewas stirred at room temperature overnight. The reaction mixtures fromthree batches were combined. DCM (15 L) and water (20 L) were added tothe reaction mixture. The aqueous layer was extracted with DCM (10 L×2).The combined organic layers were washed with brine (10 L), dried overNa₂SO₄, filtered and concentrated to give crude product. The crudeproduct was triturated with MeOH (3 L) and filtered to give the titlecompound (2950 g, 89.2% combined yield) as a yellow solid. The materialwas used for next step without further purification (6:1, PDT:SM). ¹HNMR (CDCl₃) δ 8.19 (d, J=8.0 Hz, 1H), 8.05 (d, J=5.6 Hz, 1H), 7.81 (d,J=4.0 Hz, 1H), 7.65-7.55 (m, 2H), 7.55-7.45 (m, 2H), 6.53 (d, J=4.4 Hz,1H).

Step 3: 4-Iodo-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine.This reaction was carried out in two parallel batches. To a stirredsolution of tetramethylammonium nitrate (708.8 g, 5.21 mol) in DCM (8 L)was added dropwise trifluoroacetic anhydride (1090 g, 5.21 mol) at 20°C. Then the reaction suspension was stirred at 20° C. for 1.5 hr. Thesuspension was cooled in a dry ice/acetone bath. A solution of4-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1000 g, 2.60 mol)in DCM (4 L) was added dropwise to the reaction mixture while keepingthe reaction temperature at −65° C. under N₂. The reaction was allowedto stir at −65° C. for 2 hr. Then the reaction mixture was stirred foranother 40 hr at room temperature under N₂. The reaction mixtures fromtwo batches were combined. The stirred reaction was quenched with 5%aqueous NaHCO₃ to pH=8. The DCM layer was separated and washed withwater (15 L×3). The combined water layers were extracted with DCM (25L×4). The combined organic layers were dried over Na₂SO₄ andconcentrated to give crude product. The crude product was slurried withEtOAc (20 L) overnight. The suspension was filtered and concentrated togive the title compound (1450 g, 64.9% combined yield) as a yellowsolid. The crude product was used to next step. ¹H NMR (DMSO-d₆) δ 8.88(s, 1H), 8.27 (d, J=4.0 Hz, 1H), 8.16 (d, J=7.6 Hz, 2H), 7.81-7.77 (m,1H), 7.69-7.66 (m, 2H), 6.89 (d, J=4.0 Hz, 1H).

Step 4.5-Nitro-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine.This reaction was carried out in four parallel batches. To a solution of4-iodo-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (300 g, 699mmol) in DMF (1.8 L) was added methyl2,2-difluoro-2-(fluorosulfonyl)acetate (268.57 g, 1398 mmol) and Cul(266.3 g, 1398 mmol) at room temperature. After addition, the reactionmixture was degassed and purged with N₂ three times. The mixture washeated to 110° C. and stirred for 1 hr at this temperature. The mixturewas filtered through Celite® and the filter cake was washed with EtOAc(500 mL×3). The filtrate was concentrated and the residue was purifiedby silica gel column chromatography (DCM:PE, 10:90-100:0) to give thetitle compound (830 g, 80% combined yield) as a white solid. ¹H NMR(CDCl₃) δ 8.88 (s, 1H), 8.23 (d, J=7.6 Hz, 2H), 8.10 (d, J=4.0 Hz, 1H),7.70-7.66 (m, 1H), 7.59-7.55 (m, 2H), 6.96 (d, J=2.0 Hz, 1H).

Step 5.3-iodo-1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine.This reaction was carried out in eight parallel batches. To a stirredsolution of5-nitro-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(66.5 g, 179.1 mmol) in 2-methyltetrahydrofuran:EtOH (2:1, 2520 mL) wasadded KOH (51.25 g, 913.4 mmol) at 0° C. After addition, the reactionmixture was allowed to warm to room temperature and stir for 30 min. I₂(145.47 g, 573.14 mmol) was added and stirred for another 1 hr. K₂CO₃(123.77 g, 8975.5 mmol) and CH₃I (254.2 g, 1.791 mol) were added to thereaction mixture. Then the reaction mixture was allowed to stir at roomtemperature overnight. The reaction mixture was concentrated to give aresidue. The residue was dissolved in DCM (4 L) and washed with 10% ofaqueous NaHSO₃ (2.5 L×4), washed with brine, and dried over Na₂SO₄. Theorganic layer was concentrated to give crude product, which wastriturated with MTBE (700 ml) and filtered to afford the title compound(333 g, 60% combined yield) as a yellow solid. ¹H NMR (CDCl₃) δ 8.64 (s,1H), 7.75 (s, 1H), 3.98 (s, 3H).

Step 6a:4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine:To the solution of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.50 g, 8.085 mmol) in EtOAc (25 mL) was added dropwise HCl-EtOAc (20mL) at room temperature. The mixture was stirred at room temperature for3 hr. The reaction mixture was concentrated to give the title compound(2.20 g, 130% crude yield) as a white solid. This material was usedwithout further purification.

Step 6b:cyclopentyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)methanone:To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(500 mg, 2.39 mmol) and TEA (968 mg, 9.57 mmoL) in DCM (10 mL) was addeddropwise cyclopentyl acid choride (317 mg, 2.39 mmol) while cooling inan ice/water bath. The reaction turned into a slurry and was allowed tostir at room temperature for 16 h. The reaction mixture was washed withwater, dried over Na₂SO₄, and concentrated to give the crude productwhich was purified by silica gel column chromatography (EtOAc/heptane,0:100-20:80) to give the title compound (530 mg, 72.6%) as a colourlessoil. LC/MS [M+H]=306.0. ¹H NMR (CDCl₃) δ 6.53-6.45 (m, 1H), 4.14-4.09(m, 2H), 3.64-3.54 (m, 2H), 2.95-2.80 (m, 1H), 2.55-2.20 (s, br, 2H),1.87-1.67 (m, 6H), 1.65-1.50 (m, 2H), 1.27 (s, 12H).

Step 6c:cyclopentyl(4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)methanone.A solution ofcyclopentyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)methanone(340 mg, 0.916 mmol),3-iodo-1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(308 mg, 1.01 mmol), Pd(PPh₃)₄ (106 mg, 0.0916 mmol) and K₃PO₄ (389 mg,1.83 mmol) in dioxane/H₂O (8 mL/2 mL) was heated to 60° C. and stirredfor 16 hr under N₂. The reaction mixture was diluted with water (25 mL)and extracted with EtOAc (2×25 mL). The EtOAc extracts were dried overNa₂SO₄, filtered, and concentrated to give the crude product. Twobatches were combined, which was then purified by silica gel columnchromatography (PE:EtOAc, 100:0-100:30) to give the title compound (320mg, yield: 41.3%) as a yellow solid. LC/MS [M+H]=423.1. ¹H NMR (CDCl₃) δ8.76 (s, 1H), 7.39 (s, 1H), 5.75-5.68 (m, 1H), 4.25 (m, 2H), 3.96 (s,3H), 3.85 (t, J=6 Hz, 1H), 3.75 (t, J=6 Hz, 1H), 3.05-2.85 (m, 1H), 2.40(s, br, 2H), 1.90-1.70 (m, 6H), 1.65-1.55 (m, 2H).

Step 7:(4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl)(cyclopentyl)methanone.To a solution ofcyclopentyl(4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)methanone(320 mg, 0.758 mmol) in MeOH (30 mL) and DCM (10 mL) was added Pd(OH)₂/C(42.6 mg). The mixture was then purged with hydrogen three times andstirred under hydrogen gas (50 psi) at 50° C. for 4 hr. The reactionmixture was filtered to remove the catalyst and fresh catalyst (42.6 mg)was added to the filtrate. The mixture was stirred under hydrogen (50psi) at 50° C. for 16 hr. The mixture was filtered through a pad ofCelite® and concentrated to give the crude product (320 mg) which waspurified by silica gel column chromatography (MeOH/DCM, 0:100-10:90) togive the title compound (70 mg, 23%) as an off-white solid. LC/MS[M+H]=395.0. ¹H NMR (CD₃OD) δ 7.96 (s, 1H), 7.31 (s, 1H), 4.70 (d, J=12Hz, 1H), 4.22 (d, J=12 Hz, 1H), 3.77 (s, 3H), 3.20-3.05 (m, 3H),2.73-2.65 (m, 1H), 2.07-1.47 (m, 14H).

Step 8:3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide:To an IKA vial was added(4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl)(cyclopentyl)methanone(30 mg, 0.092 mmol), 3-cyano-5-methoxybenzoic acid (0.111 mmol, 1.2 eq),2-chloromethylpyridinium iodide (23.6 mg, 0.092 mmol), DIPEA (47.7 mg,0.369 mmol) and THF (3 mL). The mixture was stirred at 70° C. for 16 hr.The reaction mixture was purified by prep-HPLC. The fractions werelyophilized to give the title compound (20 mg, 40.0%) as a white solid.LC/MS [M+H]=554.0. ¹H NMR (CDCl₃) δ 8.55 (s, 1H), 8.12 (s, 1H), 7.78 (s,1H), 7.73 (s, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 4.82 (d, J=12 Hz, 1H),4.10 (d, J=12 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.19-3.13 (m, 2H),2.95 (quint, J=8 Hz, 1H), 2.72-2.60 (m, 1H), 2.01 (dd, J=28, 12 Hz, 2H),1.85-1.45 (m, 10H).

Examples 2-4

The following Examples 2-4 were prepared analogous to Example 1employing the appropriate carboxylic acid coupling reagent in Step 6band the appropriate carboxylic acid coupling reagent in Step 8.

Ex. Structure Name/Characterization 2

3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methylbenzamide. LC/MS [M + H] = 538.0. ¹H NMR (CDCl₃) δ 8.55 (s,1H), 8.19 (s, 1H), 8.08-8.04 (m, 2 H), 7.49 (d, J = 8 Hz, 1H), 7.23 (s,1H), 4.81 (d, J = 12 Hz, 1H), 4.10 (d, J = 12 Hz, 1H), 3.90 (s, 3H),3.18-3.12 (m, 2H), 2.94 (quint, J = 8 Hz, 1H), 2.70-2.62 (m, 4H), 2.01(dd, J = 24, 13 Hz, 2H), 1.95-1.50 (m, 10H) 3

3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorobenzamide. LC/MS [M + H] = 542.0. ¹H NMR (CDCl₃) δ 8.52 (s,1H), 8.29-8.18 (m, 3H), 7.39 (t, J = 8.4 Hz, 1H), 7.25 (s, 1H), 4.80 (d,br, J = 10.8 Hz, 1H), 4.11 (d, br, J = 10.8 Hz, 1H), 3.91 (s, 3H), 3.16(t, br, J = 11.6 Hz, 2H), 2.95 (quint, J = 8.0 Hz, 1H), 2.65 (m, 1H),2.45-2.15 (m, 2H), 2.15-1.93 (m, 2H), 1.93- 1.67 (m, 4H), 1.67-1.43 (m,4H). 4

3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] = 554.0; ¹H NMR (500 MHz, CDCl₃) δ8.55 (s, 1H), 8.19-8.14 (m, 2H), 7.99 (s, 1H), 7.23 (s, 1H), 7.10 (dd, J= 3.0, 6.3 Hz, 1H), 4.84-4.77 (m, 1H), 4.12-4.06 (m, 1H), 4.03 (s, 3H),3.90 (s, 3H), 3.20-3.10 (m, 2H), 2.98-2.90 (m, 1H), 2.69-2.59 (m, 1H),2.07-2.00 (m, 1H), 2.00-1.93 (m, 1H), 1.91-1.79 (m, 4H), 1.78-1.69 (m,2H), 1.64- 1.40 (m, 4H).

Example 5 Preparation of3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1: tert-butyl4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate.This reaction was carried out in six parallel batches. To a stirredsolution of3-iodo-1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(prepared as described in Example 1, 52.5 g, 141.49 mmol) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(65.62 g, 212.2 mmol) in DME:EtOH (4:1, 1850 mL) was added Pd(PPh₃)₄(8.17 g, 7.07 mmol). After addition, the mixture was degassed threetimes with N₂. A slurry of K₂CO₃ (78.22 g, 565.95 mmol) in H₂O (141 ml)was added slowly to the reaction. After addition, the reaction mixturewas heated to 78° C. and stirred for 18 hr. The reaction mixture wasthen cooled to room temperature and poured into water. The mixture wasthen extracted with EtOAc (1 L×3), and the combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated. The resultingresidue was purified by silica gel column chromatography (EtOAc:PE,20:80-80:20) to give the title compound (270 g, 75% combined yield) as ayellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 7.37 (s, 1H),5.69-5.66 (m, 1H), 4.05-4.02 (m, 2H), 3.94 (s, 3H), 3.67-3.62 (m, 2H),2.36-2.31 (m, 2H), 1.51 (s, 9H).

Step 2:1-methyl-5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridinehydrochloride. This reaction was carried out in two batches. To asolution of tert-butyl4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate(140 g, 0.329 mol) in DCM:EtOAc (1:1, 1200 mL) was added dropwise a 4 Msolution of HCl/Dioxane (1 L) at 0° C. After addition, the mixture waswarmed to 20° C. and stirred for 3 hr. The reaction mixture was thenfiltered, and the solid was washed with MTBE (500 mL). The solid wasthen dried under vacuum to provide the hydrochloride salt of the titlecompound (182 g, 77% combined yield) as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 9.38 (br. s., 2H), 8.99 (s, 1H), 8.04 (s, 1H), 5.67-5.74 (m,1H), 3.93 (s, 3H), 3.76-3.64 (m, 2H), 3.32-3.21 (m, 2H)

Step 3:2-methyl-1-(4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-1-one.This reaction was carried out in two batches. To a solution of1-methyl-5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridinehydrochloride (91 g, 0.25 mol) in DCM (1 L) was added TEA (90 mL) andisobutyryl chloride (42 g, 0.39 mol) at 0° C. After addition, themixture was stirred at 20° C. for 14 h. The mixture was then quenchedwith water (400 mL), and the organic layer was concentrated. The crudeproduct was purified by silica gel column chromatography (DCM) toprovide the title compound (182 g, 91% combined yield) as a yellowsolid. ¹H-NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 7.38 (s, 1H), 5.74-5.65(m, 1H), 4.06-4.02 (m, 2H), 3.95 (s, 3H), 3.64-3.62 (m, 1H), 2.361-2.32(m, 2H), 1.60-1.40 (m, 9H).

Step 4a:1-(4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl)-2-methylpropan-1-one.This reaction was carried out in eighteen parallel batches. To asolution of2-methyl-1-(4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-1-one(10 g, 25.25 mmol) in EtOH (400 mL) was added Pd(OH)₂/C (5 g, 35.71mmol) at 20° C. The mixture was hydrogenated under 50 psi hydrogen gasat 50° C. for 24 hr. The mixture was filtered and the solid was washedwith DCM (1 L). The combined filtrates were concentrated under reducedpressure to give the title compound (180 g, 107% combined crude yield)as a gray solid which was used in the next step directly without furtherpurification. ¹H-NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.04 (s, 1H),4.85-4.77 (m, 1H), 4.19 (br. s., 2H), 4.07-3.98 (m, 1H), 3.78 (s, 3H),3.16-3.09 (m, 2H), 2.84-2.80 (m, 1H), 2.63-2.61 (m, 1H), 2.08-1.87 (m,2H), 1.57-1.36 (m, 2H), 1.16-1.12 (m, 6H).

Step 4b:1-(4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl)-2-methylpropan-1-onehydrochloride. To a solution of1-(4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl)-2-methylpropan-1-one(180 g, 0.49 mol) in DCM/EtOAc (400 mL/400 mL) was added dropwiseHCl/EtOAc (750 mL, 4M) at 0° C. After addition, the mixture was stirredat 20° C. for 3 h. The mixture was then filtered and the filter cakewashed with DCM (500 mL). The solid was dried under vacuum to give thetitle compound (220 g, 110% crude yield) as a yellow solid. ¹H NMR(partial, 400 MHz, DMSO-d₆) δ 8.50 (s, 1H), 7.84 (s, 1H), 3.80 (s, 3H),3.14-2.95 (m, 2H), 2.91-2.89 (m, 1H), 1.96-1.74 (m, 2H), 1.56-1.39 (m,2H), 1.10-1.01 (m, 6H). A large water peak obscured a portion of thespectrum.

Step 5:3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.This reaction was carried out in three parallel batches. To a solutionof1-(4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl)-2-methylpropan-1-one(70 g, 0.17 mol) in DCM (700 mL) was added pyridine (40 mL) and3-cyanobenzoyl chloride (31 g, 0.187 mol) at 0° C. The mixture wasstirred at 0° C. for 3 hr. The reaction was monitored by TLC (MTBE)until it was determined that the starting material was consumed, atwhich time the mixture the mixture was poured into water (300 mL). Theorganic layers were then extracted and washed with water (1 L×2). Theorganic layers were combined and concentrated to give the crude residuewhich was then suspended in EtOH (180 mL) and heated to 90° C. for 1 hr.The mixture was then cooled and the resulting precipitate was filteredand rinsed with cold EtOH (300 mL). The filter cake was then dried undervacuum to give the title compound (156 g, 62% combined yield) as a whitesolid. LC/MS [M+H]=498.2; ¹HNMR (400 MHz, CDCl₃) δ 8.50 (s, 2H),8.29-8.27 (m, 1H), 8.21-8.19 (m, 1H), 7.86-7.83 (m, 1H), 7.23 (s, 1H),4.78-4.75 (m, 1H), 4.10-4.02 (m, 1H), 3.90 (s, 3H), 3.18-3.12 (m, 2H),2.86-2.81 (m, 1H), 2.63-2.57 (m, 1H), 2.05-1.92 (m, 3H), 1.47-1.44 (m,2H), 1.15-1.10 (m, 6H); ¹³CNMR (100 MHz, DMSO-d₆) δ 174.5, 165.5, 147.0,143.9, 135.8, 135.2, 132.8, 131.9, 131.7, 130.5, 125.4, 124.6, 122.7 (q,J=278 Hz), 118.7, 117.5, 113.9, 112.2, 46.2, 42.6, 35.7, 34.5, 33.7,29.5, 20.1, 19.8, 19.0; mp=222° C.

Examples 6-13

The following Examples 6-13 were prepared analogous to Example 5employing the appropriate carboxylic acid or carboxylic acid chloridecoupling reagents in Step 5.

Ex. Structure Name/Characterization 6

3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4- methoxybenzamide.LC/MS [M + H] = 528. ¹H NMR (500 MHz, DMSO-d₆) δ 10.42 (s, NH), 8.37 (d,J = 2.2 Hz, 1H), 8.30 (dd, J = 2.2, 8.9 Hz, 1H), 8.29 (s, 1H), 7.85 (s,1H), 7.44 (d, J = 8.9 Hz, 1H), 4.63-4.55 (m, 1H), 4.13-4.05 (m, 1H),4.02 (s, 3H), 3.85 (s, 3H), 3.13-3.04 (m, 2H), 2.95-2.88 (m, 1H),2.57-2.52 (m, 1H), 1.96-1.82 (m, 2H), 1.60-1.40 (m, 2H), 1.03 (dd, J =6.4, 20.9 Hz, 6H). 7

3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4- methylbenzamide.LC/MS [M + H] = 512. ¹H NMR (500 MHz, CD₃OD) δ 8.30 (s, 1H), 8.29 (d, J= 1.7 Hz, 1H), 8.16 (dd, J = 1.9, 7.9 Hz, 1H), 7.63 (s, 1H), 7.63 (d, J= 8.2 Hz, 1H), 4.76-4.70 (m, 1H), 4.24-4.18 (m, 1H), 3.91 (s, 3H),3.44-3.38 (m, 1H), 3.26-3.20 (m, 1H), 3.05-2.98 (m, 1H), 2.74-2.66 (m,1H), 2.65 (s, 3H), 2.11-2.05 (m, 1H), 2.04-1.98 (m, 1H), 1.68-1.54 (m,2H), 1.13 (dd, J = 6.8, 19.7 Hz, 6H). 8

3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5- methoxybenzamide.LC/MS [M + H] = 528. ¹H-NMR (500 MHz, CD₃OD) δ 8.30 (s, 1H), 7.90 (t, J= 1.4 Hz, 1H), 7.83-7.81 (m, 1H), 7.63 (s, 1H), 7.55-7.53 (m, 1H),4.77-4.69 (m, 1H), 4.24-4.16 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H),3.28-3.17 (m, 2H), 3.06-2.96 (m, 1H), 2.74-2.66 (m, 1H), 2.11-2.04 (m,1H), 2.04-1.97 (m, 1H), 1.68-1.52 (m, 2H), 1.13 (dd, J = 7.1, 19.7 Hz,6H). 9

3-cyano-4-fluoro-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide.LC/MS [M + H] = 516. ¹H NMR (500 MHz, CD₃OD): δ 8.40 (dd, J = 2.3, 6.1Hz, 1H), 8.37- 8.32 (m, 1H), 8.31 (s, 1H), 7.64 (s, 1H), 7.58 (t, J =8.9 Hz, 1H), 4.76-4.70 (m, 1H), 4.24-4.17 (m, 1H), 3.91 (s, 3H),3.26-3.20 (m, 2H), 3.06-2.97 (m, 1H), 2.74- 2.66 (m, 1H), 2.11-2.05 (m,1H), 2.04-1.98 (m, 1H), 1.68-1.53 (m, 2H), 1.13 (dd, J = 6.8, 19.7 Hz,6H). 10

3-chloro-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4- methoxybenzamide.LC/MS [M + H] = 537.45. ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H), 7.99 (d,J = 1.8 Hz, 1H), 7.90-7.81 (m, 2H), 7.23 (s, 1H), 7.05 (d, J = 8.6 Hz,1H), 4.84 (d, J = 13.1 Hz, 1H), 4.06 (d, J = 13.5 Hz, 1H), 4.00 (s, 3H),3.91 (s, 3H), 3.17 (t, J = 12.2 Hz, 2H), 2.86 (dt, J = 13.5, 6.8 Hz,1H), 2.65 (t, J = 12.4 Hz, 1H), 2.11-1.97 (m, 2H), 1.55-1.42 (m, 2H),1.17 (dd, J = 9.5, 7.2 Hz, 6H). 11

4-chloro-3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide.LC/MS [M + H] = 532. ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 8.28 (br.s., 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.07 (br. s., 1H), 7.69 (d, J = 8.5Hz, 1H), 7.26 (br.s., 1H), 4.83 (d, J = 12.6 Hz, 1H), 4.42 (d, J = 1.2Hz, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.92 (s, 3H), 3.17 (t, J = 12.6 Hz,2H), 2.86 (dt, J = 13.2, 6.7 Hz, 1H), 2.64 (t, J = 12.4 Hz, 1H),2.11-1.94 (m, 2H), 1.54-1.40 (m, 1H), 1.16 (dd, J = 9.7, 7.0 Hz, 6H). 12

3-chloro-4-fluoro-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide.LC/MS [M + H] = 525.15 . ¹H NMR (400 MHz, CDCl₃) δ 8.62-8.53 (m, 1H),8.07-7.70 (m, 3H), 7.56 (d, J = 8.6 Hz, 1H), 7.26-7.21 (m, 1H), 4.83 (d,J = 12.1 Hz, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.95-3.88 (m, 3H), 3.16 (t,J = 12.1 Hz, 2H), 2.97-2.81 (m, 2H), 2.64 (t, J = 12.4 Hz, 1H),2.12-1.94 (m, 2H), 1.57-1.42 (m, 1H), 1.16 (dd, J = 9.9, 7.2 Hz, 6H). 13

3-chloro-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5- methoxybenzamide.LC/MS [M + H] = 537.45. ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 8.29(s, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.31 (t, J = 2.0 Hz,1H), 4.60 (d, J = 12.3 Hz, 1H), 4.09 (d, J = 12.8 Hz, 1H), 3.86 (s, 3H),3.82 (s, 3H), 3.09 (d, J = 7.9 Hz, 2H), 2.97-2.86 (m, 1H), 2.60-2.50 (m,1H), 1.97-1.81 (m, 2H), 1.59-1.39 (m, 2H), 0.90 (d, J = 6.6 Hz, 3H),1.03 (d, J = 6.6 Hz, 3H).

Example 14 Preparation of3-cyano-N-(3-(1-(2-cyclopentylacetyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1: tert-butyl4-(5-(3-cyanobenzamido)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate.A stirred mixture of tert-butyl4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate(prepared as described in Example 5, 1400 mg, 3.53 mmol) in EtOH (50 mL)and DCM (10 mL) was purged with N₂ and then Pd(OH)₂/C (1000 mg, 7.121mmol) was added at room temperature. The reaction mixture was stirred at50° C. under hydrogen gas (50 psi). After 4 hr, the mixture was filteredand the filtrate was concentrated. The crude product was purified bysilica gel column chromatography (PE:EtOAc, 70:30) to afford tert-butyl4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate(1.02 g, 68.3%) as a white solid which was immediately brought up in THF(50 mL). 3-cyanobenzoyl chloride (650 mg, 4.42 mmol),2-chloromethylpyridinium iodide (2050 mg, 8.03 mmol), and DIPEA (2080mg, 16.1 mmol) were added at room temperature. The mixture was thenstirred for 8 hr at ambient temperature. Upon consumption of thestarting materials as demonstrated by TLC, water was added to thereaction the mixture, and the mixture was then extracted with DCM. Theorganic layer was separated, dried over Na₂SO₄, and concentrated. Thecrude product was purified by silica gel column chromatography(PE:EtOAc, 9:1-8:2) to afford the title compound (1.3 g, 61%) as a whitesolid. ¹H-NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.24-8.18 (m, 1H),8.15-8.01 (m, 1H), 7.88-7.86 (m, 1H), 7.69-7.65 (m, 1H), 4.24 (br s,1H), 3.91 (s, 3H), 3.08-3.02 (m, 1H), 2.85-2.80 (m, 2H), 1.95-1.91 (m,2H), 1.48 (s, 9H).

Step 2:3-cyano-N-(1-methyl-3-(piperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.To the stirred solution of tert-butyl4-(5-(3-cyanobenzamido)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate(500 mg, 0.948 mmol) in DCM (10 mL) was added 4M HCl in dioxane at roomtemperature, then stirred for 1 hr at ambient temperature. The producthydrochloride was precipitated out. The solvent was removed underreduced pressure to afford the hydrochloride salt of the title compound(80 mg). LC/MS [M+H]=427.9. ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (br s, 2H),8.46 (s, 1H), 8.35-8.32 (m, 2H), 8.14-8.11 (m, 1H), 7.82-7.79 (m, 2H),3.90 (s, 3H), 3.40-3.36 (m, 2H), 3.13-3.00 (m, 3H), 2.09-1.84 (m, 4H),

Step 3:3-cyano-N-(3-(1-(2-cyclopentylacetyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.3-Cyano-N-(1-methyl-3-(piperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamidehydrochloride (80 mg, 0.152 mmol) was treated with DCM (2 mL), TEA (0.5mL, 3.59 mmol), HATU (90 mg, 0.24 mmol) and 2-cyclopentylacetic acid(0.374 mmol, 2 eq). The mixture was then stirred at room temperature for1 hr or until the reaction mixture had shown to be complete by LCMS. Thereaction mixture was concentrated. The residue was purified by silicagel column chromatography (PE:EtOAc, 70:30) to provide the titlecompound (25.9 mg, 35%) as a while solid. LC/MS [M+Na]=560.0. ¹H NMR(400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.30-8.11 (m, 2H), 8.01-7.82 (m, 2H),7.68 (t, J=7.8 Hz, 1H), 7.27-7.20 (m, 2H), 4.83 (d, J=13.1 Hz, 1H), 4.01(d, J=12.6 Hz, 1H), 3.92 (s, 3H), 3.16 (t, J=11.8 Hz, 2H), 2.72 (m, 1H),2.39-1.81 (m, 7H), 1.64-1.41 (m, 5H), 1.29-1.03 (m, 2H).

Examples 15-27

The following Examples 15-27 were prepared analogous to Example 14employing the appropriate carboxylic acid coupling reagent in Step 3.

Ex. Structure Name/Characterization 15

3-cyano-N-(1-methyl-3-(1-(3-methylbutanoyl)piperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide.LC/MS [M + Na] = 534.1. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H),8.29-8.10 (m, 2H), 7.99 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.68 (t, J =7.8 Hz, 1H), 7.24 (s, 1H), 4.84 (d, J = 15.6 Hz, 1H), 4.00 (d, J = 12.6Hz, 1H), 3.92 (s, 3H), 3.23-3.01 (m, 2H), 2.49-2.71 (m, 1H), 2.26 (d, J= 7.0 Hz, 2H), 1.86-2.20 (m, 3H), 1.36-1.61 (m, 2H), 1.00-0.88 (m, 6H).16

3-cyano-N-(1-methyl-3-(1-((2r,3aR,7aS)-octahydro-1H-indene-2-carbonyl)piperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 578.1. ¹H NMR(400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.27-8.12 (m, 2H), 7.98-7.85 (m, 2H),7.68 (t, J = 7.8 Hz, 1H), 7.25 (s, 1H), 4.84 (d, J = 15.1 Hz, 1H), 4.06(d, J = 13.6 Hz, 1H), 3.92 (s, 3H), 3.23- 2.95 (m, 3H), 2.76-2.57 (m,1H), 2.09-1.79 (m, 8H), 1.61-1.39 (m, 6H), 1.35-1.20 (m, 4H). 17

3-cyano-N-(1-methyl-4-(trifluoromethyl)-3-(1-(3,3,4-trimethylpentanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + Na] = 576.1. ¹H NMR (400 MHz,CDCl₃) δ 8.58 (s, 1H), 8.12-8.31 (m, 2H), 8.00 (br. s., 1H), 7.89 (d, J= 7.5 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.24 (s, 1H), 4.88 (d, J = 14.6Hz, 1H), 4.06 (d, J = 13.1 Hz, 1H), 3.92 (s, 3H), 3.16 (br. s., 2H),2.62 (t, J = 12.8 Hz, 1H), 2.41-2.21 (m, 2H), 2.08-1.92 (m, 3H),1.74-1.65 (m, 1H), 1.62-1.39 (m, 1H), 1.01- 0.88 (m, 12H). 18

3-cyano-N-(3-(1-(2-cyclobutylacetyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide.LC/MS [M + H] = 524.0. ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 8.25 (s,1H), 8.18 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.88 (d, J = 7.5 Hz, 1H),7.67 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 4.78 (d, J = 14.1 Hz, 1H), 3.97(d, J = 14.1 Hz, 1H), 3.91 (s, 3H), 3.20- 3.07 (m, 2H), 2.72 (dt, J =15.6, 7.8 Hz, 1H), 2.67-2.57 (m, 1H), 2.50 (d, J = 7.5 Hz, 2H),2.23-2.11 (m, 2H), 2.07-1.80 (m, 4H), 1.78-1.67 (m, 2H), 1.55-1.36 (m,2H). 19

3-cyano-N-(3-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide.LC/MS [M + H] = 538.1. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.25 (s,1H), 8.18 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.89 (d, J = 7.5 Hz, 1H),7.72-7.61 (m, 1H), 7.25 (s, 1H), 4.82 (d, J = 14.6 Hz, 1H), 4.04 (d, J =13.1 Hz, 1H), 3.91 (s, 3H), 3.24-3.07 (m, 2H), 2.70-2.43 (m, 2H),2.11-1.95 (m, 2H), 1.85- 1.69 (m, 5H), 1.62-1.41 (m, 3H), 1.35-1.15 (m,4H). 20

3-cyano-N-(3-(1-(2-cyclohexylacetyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide.LC/MS [M + H] = 552.1; ¹H NMR (400 MHz, CDCl₃) δ 8.58 (br. s., 1H),8.28-8.13 (m, 2H), 7.98 (br. s., 1H), 7.89 (d, J = 7.0 Hz, 1H), 7.68 (t,J = 7.8 Hz, 1H), 7.25 (br. s., 1H), 4.84 (d, J = 11.5 Hz, 1H), 4.00 (d,J = 11.5 Hz, 1H), 3.92 (s, 3H), 3.16 (t, J = 11.5 Hz, 2H), 2.73-2.58 (m,1H), 2.26 (d, J = 7.0 Hz, 2H), 2.10-1.94 (m, 2H), 1.86-1.63 (m, 6H),1.61-1.39 (m, 2H), 1.35-1.09 (m, 3H), 1.05-0.87 (m, 2H). 21

(R)-3-cyano-N-(1-methyl-4-(trifluoromethyl)-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + Na] = 562.1; Chiral LC: Rt = 5.26min (Method A); ¹H NMR (400 MHz, CDCl₃) δ 8.56 (br. s., 1H), 8.04-8.29(m, 3H), 7.88 (d, J = 8.0 Hz, 1H), 7.74-7.59 (m, 1H), 7.23 (s, 1H), 4.89(br. s., 1H), 4.20 (d, J = 13.1 Hz, 1H), 3.91 (s, 3H), 3.16 (t, J = 12.6Hz, 2H), 2.77-2.44 (m, 2H), 2.13- 1.83 (m, 2H), 1.54-1.31 (m, 2H),1.22-0.84 (m, 12H). 22

(S)-3-cyano-N-(1-methyl-4-(trifluoromethyl)-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + Na] = 562.1; Chiral LC: Rt = 4.91min (Method A); ¹H NMR (400 MHz, CDCl₃) δ 8.56 (br. s., 1H), 8.29-8.04(m, 3H), 7.88 (d, J = 8.0 Hz, 1H), 7.74-7.59 (m, 1H), 7.23 (s, 1H), 4.89(br. s., 1H), 4.20 (d, J = 13.1 Hz, 1H), 3.91 (s, 3H), 3.16 (t, J = 12.6Hz, 2H), 2.77-2.44 (m, 2H), 2.13- 1.83 (m, 2H), 1.54-1.31 (m, 2H),1.22-0.84 (m, 12H). 23

3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide.LC/MS [M + H] = 524.5. ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.42(s, 1H), 8.33- 8.22 (m, 1H), 8.11 (d, J = 7.4 Hz, 1H), 7.86 (s, 1H),7.79 (t, J = 7.8 Hz, 1H), 4.59 (d, J = 14.4 Hz, 1H), 4.12 (d, J = 11.3Hz, 1H), 3.93-3.74 (m, 2H), 3.17-2.95 (m, 2H), 2.74-2.52 (m, 2 H,2.05-1.35 (m, 9H), 1.35-1.08 (m, 2H). 24

3-cyano-N-(3-(1-(2-cyclopropylacetyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide.LC/MS [M + Na] = 532.1; ¹H NMR (400 MHz, CDCl₃): δ 8.54 (s, 1H),8.30-8.18 (m, 3H), 7.89- 7.86 (m, 1H), 7.68-7.64 (m, 1H), 7.27-7.24 (m,1H), 4.82-4.79 (m, 1H), 3.96-3.91 (m, 4H), 3.16-3.13 (m, 2H), 2.67-2.61(m, 1H), 2.32-2.31 (m, 2H), 2.05-1.96 (m, 2H), 1.54-1.45 (m, 2H),1.10-1.02 (m, 1H), 0.57- 0.55 (m, 2H), 0.19-0.18 (m, 2H). 25

Rac-3-cyano-N-(3-(1-(2- cyclopropylpropanoyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide. LC/MS [M +H] = 524.1; ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H), 8.48 (s, 1H),8.29-8.20 (m, 2H), 7.85-7.83 (m, 1H), 7.64-7.61 (m, 1H), 7.27- 7.22 (m,1H), 4.81-4.78 (m, 1H), 3.98-3.89 (m, 4H), 3.22-3.05 (m, 2H), 2.72-2.55(m, 1H), 2.20-1.92 (m, 3H), 1.50-1.09 (m, 6H), 0.70-0.45 (m, 2H), 0.14(br s, 2 H). 26

Rac-3-cyano-N-(1-methyl-3-(1-((1S*,2S*)-2-methylcyclopentane-1-carbonyl)piperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide. LC/MS [M +H] = 538.1; Chiral LC: Rt = 5.51 min (Method A); ¹H NMR (400 MHz, CDCl₃)δ 8.52 (s, 1H), 8.27-8.19 (m, 3H), 7.88-7.86 (m, 1H), 7.65 (m, 1H),7.25-7.23 (m, 1H), 4.84-4.81 (m, 1H), 4.12-4.08 (m, 1H), 3.91 (s, 3H),3.20-3.10 (m, 2H), 2.65-2.58 (m, 1H), 2.50-2.48 (m, 1H), 2.46-2.30 (m,1H), 2.18-1.75 (m, 4H), 1.71-1.63 (m, 3H), 1.48-1.35 (m, 2H), 1.26-1.21(m, 1H), 1.04-0.99 (m, 3H). 27

Rac-3-cyano-N-(1-methyl-3-(1-((1R*,2S*)-2-methylcyclopentane-1-carbonyl)piperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide. LC/MS [M +H] = 538.1; Chiral LC: Rt = 5.79 min (Method A); ¹H NMR (400 MHz, CDCl₃)δ 8.55 (s, 1H), 8.27-8.19 (m, 3H), 7.89-7.87 (m, 1H), 7.69-7.65 (m, 1H),7.24-7.23 (m, 1H), 4.88-4.82 (m, 1H), 4.12-4.10 (m, 1H), 3.92 (s, 3H),3.19-3.11 (m, 2H), 3.09-2.95 (m, 1H), 2.95-2.60 (m, 1H), 2.40-2.28 (m,1H), 2.27-2.15 (m, 1H), 2.13-1.91 (m, 2H), 1.90- 1.32 (m, 6H), 0.95-0.82(m, 3H).

Examples 28-29

The following Examples 28-29 were prepared analogous to Example 14employing tetrahydrothiophene-2-carboxylic acid in Step 3. The resultingracemic mixture was resolved by chiral SFC (Chiralcel OJ, 250×30 mm, 5μm; 30% MeOH; 60 mL/min). Isolation of the first eluting isomer affordedExample 28 and isolation of the second eluting isomer afforded Example29.

Ex. Structure Name/Characterization 28

(R)-3-cyano-N-(1-methyl-3-(1-(tetrahydrothiophene-2-carbonyl)piperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 542.1. Chiral SFC:Rt = 4.878 min (Method N). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H),8.25-8.17 (m, 3H), 7.89-7.85 (m, 1H), 7.66- 7.64 (m, 1H), 7.27-7.24 (m,1H), 4.78-4.74 (m, 1H), 4.07-4.00 (m, 2H), 3.91 (s, 3H), 3.20-3.14 (m,2H), 2.99-2.89 (m, 2H), 2.76-2.62 (m, 1H), 2.60-2.47 (m, 1H), 2.35-2.20(m, 1H), 2.12-1.85 (m, 4H), 1.78-1.45 (m, 2H). 29

(S)-3-cyano-N-(1-methyl-3-(1-(tetrahydrothiophene-2-carbonyl)piperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 542.1. Chiral SFC:Rt = 5.214 min (Method N). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H),8.25-8.17 (m, 3H), 7.89-7.85 (m, 1H), 7.66-7.64 (m, 1H), 7.27-7.24 (m,1H), 4.78-4.74 (m, 1H), 4.07-4.00 (m, 2H), 3.91 (s, 3H), 3.20-3.14 (m,2H), 2.99-2.89 (m, 2H), 2.76-2.62 (m, 1H), 2.60-2.47 (m, 1H), 2.35-2.20(m, 1H), 2.12-1.85 (m, 4H), 1.78-1.45 (m, 2H).

Examples 30-31

The following Examples 30-31 were prepared analogous to Example 14however employing 3-cyano-4-methoxybenzoic acid in Step 1.

Ex. Structure Name/Characterization 30

(R)-3-cyano-4-methoxy-N-(1-methyl-4-(trifluoromethyl)-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 570.2;Chiral LC: Rt = 7.01 min (Method A); ¹H NMR (400 MHz, CDCl₃) δ 8.54 (br.s., 1H), 8.18 (br. s., 2H), 8.03 (br. s., 1H), 7.22 (s, 1H), 7.11 (d, J= 6.5 Hz, 1H), 4.90 (br. s., 1H), 4.20 (d, J = 13.1 Hz, 1H), 4.04 (s,3H), 3.99 (s, 3H), 3.15 (t, J = 12.3 Hz, 2H), 2.80-2.46 (m, 2H),2.12-1.89 (m, 2H), 1.75-1.32 (m, 2H), 1.24-0.72 (m, 12H). 31

(S)-3-cyano-4-methoxy-N-(1-methyl-4-(trifluoromethyl)-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 570.2; Chiral LC:Rt = 6.43 min (Method A); ¹H NMR (400 MHz, CDCl₃) δ 8.54 (br. s., 1H),8.18 (br. s., 2H), 8.03 (br. s., 1H), 7.22 (s, 1H), 7.11 (d, J = 6.5 Hz,1H), 4.90 (br. s., 1H), 4.20 (d, J = 13.1 Hz, 1H), 4.04 (s, 3H), 3.99(s, 3H), 3.15 (t, J = 12.3 Hz, 2H), 2.80-2.46 (m, 2H), 2.12-1.89 (m,2H), 1.75-1.32 (m, 2H), 1.24-0.72 (m, 12H).

Example 32 Preparation of(R)-3-cyano-N-(1,4-dimethyl-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1: 4-methyl-1H-pyrrolo[2,3-b]pyridine. A solution of MeMgBr (655mL, 1.97 mol, 3 M in ether) was added dropwise to a stirred suspensionof 4-chloro-1H-pyrrolo[2,3-b]pyridine (60 g, 393.2 mmol) and Pd(dppf)Cl₂(5.75 g, 7.86 mmol) in toluene (1200 mL) at room temperature under N₂.After addition, the reaction mixture was purged with N₂ for severaltimes and then was heated at 80° C. for 3.5 hr. The reaction mixture wascooled to room temperature and poured into ice-water slowly. Afterstanding overnight, the mixture was filtered and further washed withEtOAc several times. The filtrate was extracted with EtOAc (2×5 L). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was triturated with PE to give the titlecompound (48.2 g, 93%) as a off-yellow solid. ¹HNMR (400 MHz, CDCl₃) δ11.27 (br. s., 1H), 8.25-8.23 (m, 1H), 7.37-7.35 (m, 1H), 6.93-6.91 (m,1H), 6.55-6.53 (m, 1H), 2.60 (s, 3H).

Step 2: 4-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. Bu₄NBr(9.14 g, 28.4 mmol), KOH (63.6 g, 1.134 mol, 33% in water) and PhSO₂Cl(160 g, 908 mmol) were added to a stirred solution of4-methyl-1H-pyrrolo[2,3-b]pyridine (75 g, 567 mmol) in DCM (1600 mL) atroom temperature. The reaction mixture was stirred at room temperaturefor 2.5 hr. The mixture was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was triturated with MTBE to afford the titlecompound (112 g, 72.7%) as a brown solid. ¹HNMR (400 MHz, CDCl₃) δ8.32-8.30 (m, 1H), 8.21-8.15 (m, 2H), 7.70-7.68 (m, 1H), 7.58-7.52 (m,1H), 7.50-7.42 (m, 2H), 6.99-6.97 (m, 1H), 6.63-6.61 (m, 1H), 2.48 (s,3H).

Step 3: 4-methyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. Asolution of tetrabutylammonium nitrate (201 g, 661 mmol) in DCM (400 mL)was added dropwise to a stirred solution of4-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (120 g, 441 mmol)in DCM (1600 mL) at −10° C. (CF₃CO)₂O (139 g, 661 mmol) was then addeddropwise at −5° C. and the mixture was stirred at 0° C. for 20 min. Thereaction mixture were washed with water (7 L), dried over Na₂SO₄ andconcentrated. The residue was triturated with MTBE to afford the titlecompound (89.1 g, 63.7%) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ9.05 (s, 1H), 8.22-8.20 (m, 2H), 7.88-7.87 (m, 1H), 7.71-7.59 (m, 1H),7.58-7.46 (m, 2H), 6.79-6.78 (m, 1H), 2.78 (s, 3H).

Step 4: 4-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine. Potassium carbonate(43.8 g, 316 mmol) and morpholine (138 g, 1.58 mol) were added to astirred suspension of4-methyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (50 g, 158mmol) in MeOH (1.8 L) at room temperature. The mixture was heated atreflux for 10 min. The reaction mixture was then cooled to roomtemperature and most of the MeOH was removed under vacuum. To theresidue was added DCM (1 L), sat. NH₄Cl (1 L) and water (0.5 L). Themixture was stirred at room temperature for 30 min and left standingovernight. The resulting solids were filtered, washed with water and DCMseveral times, and dried to afford the title compound (25 g, 89.7%) asan off-yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ 12.35 (br. s., 1H), 8.90(s, 1H), 7.69-7.67 (m, 1H), 6.86-6.84 (m, 1H), 2.81 (s, 3H).

Step 5: 1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine. Potassiumcarbonate (80 g, 576 mmol) and iodomethane (123 g, 864 mmol) were addedto a stirred suspension of 4-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine(34 g, 192 mmol) in DMF (600 mL) at room temperature. The mixture wasstirred at room temperature for 3 hr. The reaction mixture was thenpoured into water (5 L), stirred at room temperature for 20 min andfiltered. The filtrate was extracted with EtOAc (2×3 L). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The solid from filtration and the residue from thefiltrate were combined and purified by silica gel column chromatography(DCM) to provide the title compound (26.5 g, 71%) as a yellow solid.¹HNMR (400 MHz, CDCl₃) δ 9.06 (s, 1H), 7.30-7.28 (m, 1H), 6.67-6.65 (m,1H), 3.93 (s, 3H), 2.86 (s, 3H).

Step 6: 3-iodo-1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine.N-Iodosuccinimide (49.5 g, 220 mmol) was added to a stirred suspensionof 1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (35 g, 183 mmol) inDMF (400 mL) at room temperature. The mixture was stirred at roomtemperature for 1 hr. The reaction mixture was then poured into water (3L), stirred at room temperature for 20 min, and was then filtered. Theresulting solid was washed with water and MTBE several times and thendried to afford the title compound (52.6 g, 90%) as a yellow solid.¹HNMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 7.96 (s, 1H), 3.81 (s, 3H),2.96 (s, 3H).

Step 7: tert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate.To a stirred suspension of3-iodo-1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (4.5 g, 14 mmol)and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(7.85 g, 56.8 mmol) in 1,2-dimethoxyethane:ethanol (4:1, 150 mL) wereadded K₂CO₃ (7.85 g, 56.8 mmol) and Pd(PPh₃)₄ (0.82 g, 0.71 mmol) atroom temperature under N₂. The mixture was degassed with N₂ severaltimes and then was heated at refluxing for 2 hr. The reaction mixturewas cooled to room temperature and poured into sat. NH₄Cl (500 mL). Themixture was extracted with EtOAc (2×500 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated. The residuewas triturated with EtOAc and filtered. The filtrate was concentratedand the resulting residue was purified by silica gel columnchromatography (EtOAc:DCM, 0:100-30:70) to afford the title compound(2.1 g, 40%) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.97 (s, 1H),7.09 (s, 1H), 5.74 (br. s., 1H), 4.07-4.06 (m, 2H), 3.88 (s, 3H),3.66-3.65 (m, 2H), 2.80 (s, 3H), 2.40 (br. s., 2H), 1.51 (s, 9H).

Step 8: tert-butyl4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate.To a Parr vessel charged with tert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate(390 mg, 1.05 mmol) and TEA (0.22 μL, 1.58 mmol) in MeOH (4 mL) wasadded 10% Pd/C (112 mg, 0.11 mmol). The vessel was sealed, itsatmosphere replaced with hydrogen gas (100 psi) and shaken for 6 hr. Thereaction mixture was then filtered through a pad of Celite® and rinsedwith MeOH (2 mL). The filtrate was then concentrated under reducedpressure to afford the title compound (361 mg, 100%) as a colorless oilwhich was not purified further. ¹HNMR (400 MHz, CD₃OD) δ 7.80 (s, 1H),6.97 (s, 1H), 4.16 (d, J=13.3 Hz, 2H), 3.66 (s, 3H), 3.27 (t, J=1.6 Hz,2H), 3.14 (t, J=11.7 Hz, 1H), 2.89 (br. s., 2H), 2.47 (s, 3H), 1.97 (d,J=13.3 Hz, 2H), 1.55-1.45 (m, 2H), 1.44 (s, 9H).

Step 9: tert-butyl4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate.TEA (0.437 mL, 3.14 mmol) and 3-cyanobenzoyl chloride (208 mg, 1.26mmol) were added successively to a solution of tert-butyl4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate(361 mg, 1.05 mmol) in DCM (10 mL) at 0° C. The mixture was stirred at0° C. for 15 min, then the ice bath was removed, and the solution wasstirred at room temperature. After complete consumption of the startingmaterial as determined by TLC, the reaction was quenched with sat.NaHCO₃ and extracted with DCM three times. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (80:20 Heptane: EtOAc) to afford the title compound (472mg, 95%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.38 (s, 1H),8.34-8.29 (m, 1H), 8.12 (s, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.79-7.71 (m,1H), 7.23 (s, 1H), 4.21 (d, J=11.7 Hz, 2H), 3.81 (s, 3H), 3.31-3.22 (m,1H), 2.93 (s, 2H), 2.63 (s, 3H), 2.06 (d, J=11.7 Hz, 2H), 1.65-1.52 (m,2H), 1.48 (s, 9H).

Step 10:3-cyano-N-(1,4-dimethyl-3-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.To a stirred solution of tert-butyl4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate(500 mg, 1.05 mmol) in DCM (10 mL) was added a solution of HCl/dioxane(4N, 10 mL) at room temperature. The mixture was stirred for 1 hr atambient temperature. The solvent was removed from the resultingprecipitate under reduced pressure to afford the hydrochloride salt ofthe title compound (430 mg, 99%). LC/MS [M+H+]=374.0; ¹H NMR (400 MHz,DMSO-d₆) δ 10.52 (s, 1H), 9.21-9.19 (m, 1H), 9.07-9.05 (m, 1H), 8.51 (s,1H), 8.37-8.35 (m, 1H), 8.21 (s, 1H), 8.10-8.08 (m, 1H), 7.80-7.75 (m,1H), 7.42 (s, 1H), 3.56 (s, 3H), 3.36-3.32 (m, 2H), 2.56 (s, 3H),2.09-2.06 (m, 2H), 1.88-1.79 (m, 2H).

Step 11:(R)-3-cyano-N-(1,4-dimethyl-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.3-Cyano-N-(1,4-dimethyl-3-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamidehydrochloride (350 mg, 0.78 mmol) was treated with DMF (2.6 mL), DIPEA(1.38 mL, 7.84 mmol), HATU (392 mg, 1.02 mmol), and(−)-(R)-2,3,3-trimethylbutanoic acid (Kido, M.; Sugiyama, S.; Satoh, T.Tetrahedron: Assym 2007, 18, 1934-47.) (133 mg, 1.02 mmol). The reactionmixture was stirred at room temperature for 1 hr. The mixture wasconcentrated and the residue was purified by silica gel columnchromatography (40:60, Heptane:EtOAc) to afford the title compound (336mg, 92%). LC/MS [M+H]=486.1; Chiral LC: Rt=3.50 min (Method B); ¹H NMR(CDCl₃) δ 8.51 (br s, 1H), 8.29-8.2 1 (m, 3H), 7.89-7.86 (m, 1H),7.70-7.65 (m, 1H), 6.96-6.92 (m, 1H), 4.86-4.75 (m, 1H), 4.23-4.19 (m,1H), 3.82 (s, 3H), 3.22-3.12 (m, 2H), 2.74-2.62 (m, 5H), 2.14-2.04 (m,2H), 1.63-1.00 (m, 14H).

Examples 33-43, 109 & 110

The following Examples 33-43, 109 and 110 were prepared analogous toExample 32 employing the appropriate carboxylic acid or carboxylic acidchloride coupling reagents in Steps 9 and 11.

Ex. Structure Name/Characterization 33

3-cyano-N-(3-(1-(2-fluoro-6-methylbenzoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide. LC/MS [M + H]= 510; ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 8.21-8.19 (m, 2H),8.04-7.99 (m, 1H), 7.84-7.82 (m, 1H), 7.64-7.60 (m, 1H), 7.23-7.21 (m,1H), 7.08-6.90 (m, 3H), 4.98-4.94 (m, 1H), 3.82 (s, 3H), 3.60-3.57 (m,1H), 3.27-3.24 (m, 2H), 3.18-3.12 (m, 2H), 2.96-2.92 (m, 1H), 2.57 (s,3H), 2.28 (s, 3H), 2.20-2.14 (m, 1H), 2.04-1.96 (m, 1H), 1.69-1.43 (m,3H). 34

3-cyano-N-(3-(1-(2,3-dihydro-1H-indene-4-carbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 518.; ; ¹H NMR (400 MHz,DMSO-d₆) δ 8.27 (s, 1H), 8.21-8.19 (m, 2H), 8.10 (s, 1H), 7.84-7.82 (m,1H), 7.63-7.61 (m, 1H), 7.23-7.17 (m, 1H), 7.15-7.13 (m, 1H), 7.07- 7.05(m, 1H), 6.96 (s, 1H), 4.98-4.94 (m, 1H), 3.83 (s, 3H), 3.73-3.70 (m,1H), 3.27-3.14 (m, 2H), 2.96-2.80 (m, 5H), 2.57 (s, 3H), 2.15-1.96 (m,4H), 1.51-1.48 (m, 2H). 35

N-(3-(1-((1R,2S,4S)-bicyclo[2.2.1]heptane-2-carbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-cyanobenzamide. LC/MS [M + H] = 496.2; Chiral LC: Rt =2.47 min (Method I); ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.08 (m, 4H),7.87-7.85 (m, 1H), 7.68-7.64 (m, 1H), 6.93-6.90 (m, 1H), 4.84-4.76 (m,1H), 4.17-4.14 (m, 1H), 3.83 (s, 3H), 3.21-3.14 (m, 2H), 2.98-2.95 (m,1H), 2.68-2.60 (m, 4H), 2.43- 2.39 (m, 1H), 2.28 (s, 1H), 2.14-1.36 (m,12H). 36

N-(3-(1-((1S,2R,4R)-bicyclo[2.2.1]heptane-2-carbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-cyanobenzamide. LC/MS [M + H] = 496.2; Chiral LC: Rt =1.57 min (Method H); ¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.32-8.30(m, 1H), 8.12 (s, 1H), 7.99-7.97 (m, 2H), 7.76-7.73 (m, 1H), 7.23 (s,1H), 4.74-4.72 (m, 1H), 4.27-4.24 (m, 1H), 3.80 (s, 3H), 3.40-3.27 (m,2H), 3.24-3.11 (m, 1H), 2.80-2.64 (m, 1H), 2.64-2.49 (m, 1H), 2.26 (s,3H), 2.26-2.10 (m, 3H), 1.86-1.85 (m, 1H), 1.59-1.32 (m, 9H). 37

(R)-3-cyano-N-(3-(1-(2,3-dimethylbutanoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide. LCMS [M + H]= 472.2. Chiral LC: Rt = 2.4 min (Method A); ¹H NMR (400 MHz, CD₃OD) δ8.38 (d, J = 1.6 Hz, 1H), 8.26-8.36 (m, 1H), 8.13 (s, 1H), 7.94-8.03 (m,1H), 7.75 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1H), 4.75 (d, J =14.0 Hz, 1H), 4.26 (d, J = 12.9 Hz, 1H), 3.81 (s, 2H), 3.39 (t, J = 12.1Hz, 1H), 2.72-2.86 (m, 2H), 2.58-2.71 (m, 3H), 2.08-2.24 (m, 2H), 1.87(d, J = 7.0 Hz, 1H), 1.60 (dd, J = 11.5, 8.8 Hz, 2H), 1.09 (dd, J =13.9, 6.8 Hz, 3H), 0.83-1.01 (m, 5H). 38

(R)-3-cyano-N-(1,4-dimethyl-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] = 516.2; Chiral LC: Rt= 6.69 (Method C); ¹H NMR (400 MHz, CDCl₃) δ 8.06-8.33 (m, 3H), 7.92(br. s., 1H), 7.09 (d, J = 6.5 Hz, 1H), 6.78-6.96 (m, 1H), 4.71-4.91 (m,1H), 4.21 (d, J = 13.1 Hz, 1H), 4.03 (s, 3H), 3.82 (s, 3H), 3.19 (d, J =12.1 Hz, 2H), 2.46-2.79 (m, 5H), 1.88- 2.16 (m, 2H), 1.38-1.69 (m, 2H),1.13 (dd, J = 13.1, 6.5 Hz, 3H), 0.99 (s, 9H). 39

(R)-3-cyano-N-(1,4-dimethyl-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide. LC/MS [M + H] = 516.1; Chiral LC: Rt= 6.42 min (Method C); ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J = 13.6 Hz,1H), 7.70- 7.92 (m, 2H), 7.33 (br. s., 1H), 6.75-6.94 (m, 1H), 4.67-4.94(m, 1H), 4.21 (d, J = 13.6 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.18 (d,J = 8.0 Hz, 2H), 2.41-2.77 (m, 5H), 1.85-2.14 (m, 2H), 1.35-1.73 (m,3H), 1.11- 1.20 (m, 3H), 0.99 (s, 9H). 40

(R)-5-cyano-N-(1,4-dimethyl-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxybenzamide. LC/MS [M + H] = 516.1; Chiral LC: Rt= 6.42 min (Method C); ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.64 (s,1H), 8.38 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H),6.95 (s, 1H), 4.90 (d, J = 13.1 Hz, 1H), 4.22 (d, J = 13.1 Hz, 4H), 3.84(s, 3H), 3.05-3.33 (m, 2H), 2.47-2.76 (m, 5H), 2.00-2.20 (m, 2H),1.45-1.69 (m, 3H), 1.12 (br. s., 3H), 1.01 (d, J = 14.1 Hz, 9H). 41

(R)-5-chloro-N-(1,4-dimethyl-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorobenzamide. LC/MS [M + H] = 513.1. Chiral SFC: Rt= 2.043 min (Method P). ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H),8.19-8.17 (m, 2H), 7.53-7.50 (m, 1H), 7.22-7.17 (m, 1H), 6.95 (s, 1H),4.92-4.88 (m, 1H), 4.24-4.20 (m, 1H), 3.84 (s, 3H), 3.27-3.16 (m, 2H),2.73-2.62 (m, 5H), 2.10-2.05 (m, 2H), 1.63-1.46 (m, 2H), 1.14-1.09 (m,3H), 1.02- 0.99 (m, 9H). 42

(R)-3-chloro-N-(1,4-dimethyl-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide. LC/MS [M + H] = 525.2. Chiral SFC:Rt = 6.072 min (Method Q). ¹H NMR (400 MHz CDCl₃) δ 8.24 (s, 1H),7.81-7.76 (m, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.10 (s, 1H), 6.93 (s,1H), 4.89-4.84 (m, 1H), 4.24-4.19 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H),3.25-3.14 (m, 2H), 3.72-3.59 (m, 5H), 2.12-2.05 (m, 2H), 1.55-1.47 (m,2H), 1.13-1.11 (m, 3H), 1.09-0.98 (m, 9H). 43

(R)-3-cyano-N-(1,4-dimethyl-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-methoxyethoxy)benzamide. LC/MS [M + Na] = 582.3;Chiral LC: Rt = 6.34 min (Method V); ¹H NMR (400 MHz, CDCl₃) δ 8.25-8.15(m, 3H), 7.83- 7.73 (m, 1H), 7.15-7.12 (m, 1H), 6.94-6.92 (m, 1H),4.89-4.84 (m, 1H), 4.40-4.30 (m, 2H), 4.25-4.15 (m, 1H), 3.90-3.85 (m,2H), 3.82 (s, 3H), 3.50 (s, 3H), 3.25-3.15 (m, 2H), 2.75-2.60 (m, 5H),2.15-1.95 (m, 2H), 1.55-1.35 (m, 2H), 1.15-1.05 (m, 3H), 1.05-0.95 (m,9H). 109

3-cyano-N-(1,4-dimethyl-3-(1-(3-methylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin- 5-yl)benzamide.LC/MS [M + H] = 458.1; 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1 H), 8.33 (s,1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.17 (s, 1 H), 7.79 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1 H), 6.87 (s, 1 H), 4.68 (d, J = 13.2 Hz, 1H), 3.99 (d, J = 13.2 Hz, 1 H), 3.79 (s, 3 H), 3.41- 3.27 (m, 2 H),2.65-2.57 (m, 1 H), 2.55 (s, 3 H), 2.23 (d, J = 7.2 Hz, 2 H), 2.11-2.04(m, 2 H), 1.91 (d, J = 13.6 Hz, 1 H), 1.55-1.47 (m, 1 H), 1.34-1.21 (m,1 H), 0.96 (d, J = 6.0 Hz, 6 H). 110

3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] =458.1; 1H NMR (400 MHz, CDCl3) δ 8.25-8.15 (m, 3H), 7.83-7.73 (m, 1H),7.15-7.12 (m, 1H), 6.94-6.92 (m, 1H), 4.89-4.84 (m, 1H), 4.40-4.30 (m,2H), 4.25-4.15 (m, 1H), 3.90-3.85 (m, 2H), 3.82 (s, 3H), 3.50 (s, 3H),3.25-3.15 (m, 2H), 2.75-2.60 (m, 5H), 2.15-1.95 (m, 2H), 1.55-1.35 (m,2H), 1.15-1.05 (m, 3H), 1.05-0.95 (m, 9H).

Examples 44-45 & 111

The following Examples 44-45 and 111 were prepared analogous to Example32 employing the appropriate carboxylic acid or carboxylic acid chloridecoupling reagents in Steps 9 and rac-3,3,3-trifluoro-2-methylpropanoicacid in Step 11. Although the enantiomers were separatedchromatographically, the absolute configuration has been arbitrarilyassigned. The enantiomers were obtained through chiral chromatographicseparation (Chiralpak AD-3 100×4.6 mm ID, 3 μm, EtOH/CO₂, 0.05% DEA, 20to 80%, 2.5 mL/min).

Ex. Structure Name/Characterization 44

(R)-3-cyano-N-(1,4-dimethyl-3-(1-(3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] = 528.5; Chiral LC: Rt= 6.29 min (Method G); ¹H NMR (400 MHz, CDCl₃) δ 8.54 (br. s., 1 H),8.18 (br. s., 1 H), 8.03 (br. s., 1 H), 7.22 (s, 1 H), 7.11 (d, J = 6.5Hz, 1 H), 4.90 (br. s., 1 H), 4.20 (d, J = 13.1 Hz, 1 H), 4.04 (s, 3 H),3.99 (s, 3 H), 3.15 (t, J = 12.3 Hz, 2 H), 2.80-2.46 (m, 3 H), 2.12-1.89(m, 5 H), 1.75-1.32 (m, 2 H), 1.24- 0.72 (m, 3 H). 45

(S)-3-cyano-N-(1,4-dimethyl-3-(1-(3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] = 528.6; Chiral LC: Rt= 7.28 min (Method G); ¹H NMR (400 MHz, CDCl₃) δ 8.54 (br. s., 1 H),8.18 (br. s., 1 H), 8.03 (br. s., 1 H), 7.22 (s, 1 H), 7.11 (d, J = 6.5Hz, 1 H), 4.90 (br. s., 1 H), 4.20 (d, J = 13.1 Hz, 1 H), 4.04 (s, 3 H),3.99 (s, 3 H), 3.15 (t, J = 12.3 Hz, 2 H), 2.80-2.46 (m, 3 H), 2.12-1.89(m, 5 H), 1.75-1.32 (m, 2 H), 1.24- 0.72 (m, 3 H). 111

(R)-3-cyano-N-(1,4-dimethyl-3-(1-(3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + 2H+] = 475.6; 1H NMR (400 MHz,CDCl3) δ ppm 8.37 (br. s., 1 H) 8.27 (d, J = 11.3 Hz, 3 H)7.10 (d, J =9.4 Hz, 1 H) 6.95 (s, 1 H) 4.79 (d, J = 11.7 Hz, 1 H) 4.01 (br. s.,4 H)3.93 (s, 3 H) 3.71 (s, 1 H) 3.07-3.30 (m, 2 H) 2.77-2.95 (m, 1 H)2.51-2.67 (m, 3 H) 1.93-2.18 (m, 4 H) 1.36-1.63 (m, 2 H) 1.04-1.24 (m, 6H).

Examples 46-47

The following Examples 46-47 were prepared analogous to Example 32employing the 3-cyanobenzoyl chloride in Steps 9 and2-methylcyclopentane-1-carboxylic acid in Step 11. The resultingtrans-isomers were resolved by chiral SFC (ChiralCel IA, 21×250 mm, 5μM; CO₂/MeOH, 60/40; 75 mL/min). Isolation of the first eluting isomerafforded Example 46 and isolation of the second eluting isomer affordedExample 47.

Ex. Structure Name/Characterization 46

3-cyano-N-(1,4-dimethyl-3-(1-((1S,2S)-2-methylcyclopentane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 484.4; Chiral LC:Rt = 3.27 min (Method AA); ¹H NMR (400 MHz, CDCl₃) δ 8.61-8.16 (m, 4H),7.90-7.80 (m, 1H), 7.69-7.58 (m, 1H), 6.95-6.84 (m, 1H), 4.84-4.67 (m,1H), 4.13-4.06 (m, 1H), 3.81 (s, 3H), 3.25-3.09 (m, 2H), 3.06-2.92 (m,0.5H), 2.71-2.62 (m, 1H), 2.59 (s, 3H), 2.54-2.45 (m, 0.5H), 2.40-2.26(m, 1H), 2.23-1.65 (m, 7.5H), 1.59-1.14 (m, 2.5H), 1.04-1.00 (m, 1.75H),0.94-0.90 (m, 0.75H), 0.86-0.79 (m, 0.75H). 47

3-cyano-N-(1,4-dimethyl-3-(1-((1R,2R)-2-methylcyclopentane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H]: 484.4; Chiral LC:Rt = 3.81 min (Method AA); ¹H NMR (400 MHz, CDCl₃) δ 8.61-8.16 (m, 4H),7.90-7.80 (m, 1H), 7.69-7.58 (m, 1H), 6.95-6.84 (m, 1H), 4.84-4.67 (m,1H), 4.13-4.06 (m, 1H), 3.81 (s, 3H), 3.25-3.09 (m, 2H), 3.06-2.92 (m,0.5H), 2.71-2.62 (m, 1H), 2.59 (s, 3H), 2.54-2.45 (m, 0.5H), 2.40-2.26(m, 1H), 2.23-1.65 (m, 7.5H), 1.59-1.14 (m, 2.5H), 1.04-1.00 (m, 1.75H),0.94-0.90 (m, 0.75H), 0.86-0.79 (m, 0.75H).

Examples 48-49

The following Examples 48-49 were prepared analogous to Example 32employing the 3-cyanobenzoyl chloride in Steps 9 and eithercis-2-isopropylcyclopentane-1-carboxylic acid (Bigi, M. A. et al, NatureChemistry 2011, 3, 216-22) or trans-2-isopropylcyclopentane-1-carboxylicacid (Yang, D. et al, Tetrahedron: Asym. 2003, 14, 2927-2937) in Step11.

Ex. Structure Name/Characterization 48

3-cyano-N-(3-(1-((1R,2R)-2-isopropylcyclopentane-1-carbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 512.2; Chiral LC: Rt = 7.66min (Method X, second eluting enantiomer); ¹H NMR (400 MHz, CDCl₃) δ8.35- 8.17 (m, 3H), 7.88-7.86 (m, 1H), 7.68-7.65 (m, 1H), 6.95-6.89 (m,1H), 4.83-4.76 (m, 1H), 4.19-4.15 (m, 1H), 3.83 (s, 3H), 3.25-3.15 (m,2H), 2.68-2.59 (m, 3H), 2.15-1.45 (m, 14H), 1.26 (s, 1H), 0.93-0.83 (m,5H). 49

3-cyano-N-(3-(1-((1R,2S)-2-isopropylcyclopentane-1-carbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 512.2; Chiral LC: Rt = 7.36min (Method X, second eluting enantiomer); ¹H NMR (400 MHz, CDCl₃) δ8.31- 8.25 (m, 3H), 8.05 (s, 0.5H), 7.88-7.86 (m, 1H), 7.69- 7.64 (m,1H), 6.96-6.92 (m, 1H), 4.82-4.79 (m, 1H), 4.17-4.14 (m, 1H), 3.82 (s,3H), 3.24-3.16 (m, 2H), 2.73-2.59 (m, 5H), 2.40-2.30 (m, 1H), 2.10-1.75(m, 4H), 1.68-1.47 (m, 5H), 1.26-1.15 (m, 2H), 0.91-0.85 (m, 6H).Absolute configuration established by X-ray co- crystallization.

Example 50 Preparation of(R)—N-(3-(1-(2-(bicyclo[1.1.1]pentan-1-yl)propanoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-cyanobenzamide

Step 1: 2-(bicyclo[1.1.1]pentan-1-yl)acetic acid. This acid was preparedaccording to the literature procedure with some modifications(Kaszynski, P.; McMurdie, N. D.; Michl, J. J. Org. Chem. 1991, 56, 307).To a stirred suspension of 1,1-dibromo-2.2-bis(chloromethyl)cyclopropane(3.0 g, 9.1 mmol) in pentane (10 mL) at −78° C. was added slowly MeLi(1.6 M in Et₂O, 14.2 mL, 22.7 mmol). The resulting yellow mixture wasstirred for 15 min at the same temperature, and then the dry ice-acetonebath was replaced with ice-water bath. The reaction was allowed to stirat 0° C. After 1 hr, the cold bath was removed and the pale yellowreaction mixture was heated to 40° C. The volatile material wasdistilled into a flask cooled in a dry ice-acetone bath withintermittent application of low vacuum. After warming the distillate to0° C., bromo methylacetate (1.44 g, 0.888 mL, 9.1 mmol) and Et₂O (10 mL)were added. The resulting clear solution at 0° C. was passed through aflow reactor irradiated with medium pressure Hanovia lamp. After 3 hr,the solution was collected in a flask and concentrated in vacuo toobtain methyl 2-(3-bromobicyclo[1.1.1]pentan-1-yl)acetate. The crudeproduct was taken up in toluene (5.0 mL). Tributyltin hydride (2.3 mL)and 2,2′-azobisisobutyronitrile (8.0 mg, 0.05 mmol) were added. Theresulting clear solution was heated at 80° C. After 2 hr, carbontetrachloride (0.77 mL) was added and the reaction was stirred for 30min to destroy the excess tributyltin hydride. Subsequently 10% NaOH inMeOH (8 mL) was added, and the reflux condenser was removed to allowMeOH to evaporate. After another 30 min, the reaction was cooled toambient temperature and quenched with H₂O (15 mL). The reaction mixturewas extracted with Et₂O (3×5 mL). The remaining yellow aqueous layer wasacidified with conc. HCl, and then extracted with EtOAc (3×15 mL). Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purified bysilica gel column chromatography (MeOH:DCM, 2:98-20:80) to provide thetitle compound as a colorless oil (364 mg, 35% over 4 steps). LC/MS[M−H]=125.1, ¹H NMR (400 MHz, CDCl₃) δ 2.52 (s, 2H), 2.50 (s, 1H), 1.83(s, 7H).

Step 2:(R)-3-(2-(bicyclo[1.1.1]pentan-1-yl)acetyl)-4-isopropyloxazolidin-2-one.To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)acetic acid (160 mg, 1.27mmol) and DMF (2.8 mg, 0.04 mmol) in DCM (1.3 mL) at 0° C. was addedthionyl chloride (0.112 mL, 1.52 mmol). The resulting pale yellowsolution was stirred at ambient temperature for 3 hr, and then thereaction mixture was carefully concentrated in vacuo to afford thecorresponding acid chloride as a yellow oil. In a separate flask, n-BuLi(2.5 M in hexanes, 0.608 mL, 1.52 mmol) was added dropwise to a solutionof (R)-(−)-4-Isopropyl-2-oxazolidinone (196 mg, 1.52 mmol) in THF (5.0mL) at −78° C. After stirring for 30 min, a solution of the above acidchloride in THF (1.0 mL) was added slowly. The resulting mixture wasstirred for 1 hr at the same temperature. The reaction was quenched withsaturated aqueous NaHCO₃ solution (5.0 mL), extracted with EtOAc (3×5mL), washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified using silica gel columnchromatography (EtOAc:Heptane, 7:93-40:60) to provide the title compound(93.5 mg, 32%). LC/MS [M+H]=238.1, ¹H NMR (400 MHz, CDCl₃) δ 4.40 (dt,J=8.0, 3.4 Hz, 1H), 4.14-4.26 (m, 2H), 3.21 (d, J=14.8 Hz, 1H), 3.01 (d,J=14.8 Hz, 1H), 2.46 (s, 1H), 2.29-2.39 (m, 1H), 1.79 (s, 6H), 0.88 (dd,J=13.7, 7.0 Hz, 6H).

Step 3:(R)-3-((R)-2-(bicyclo[1.1.1]pentan-1-yl)propanoyl)-4-isopropyloxazolidin-2-one.To a solution of(R)-3-(2-(bicyclo[1.1.1]pentan-1-yl)acetyl)-4-isopropyloxazolidin-2-one(93.5 mg, 0.394 mmol) in THF (2.5 mL) at −78° C. was added dropwise LDA(2.0 M in THF, 0.227 mL, 0.453 mmol). The resulting yellow solution wasstirred for 1 hr, and then iodomethane (280 mg, 0.124 mL, 1.97 mmol) wasadded slowly. The reaction was allowed to stir at −78° C. for 8 hr, andthen warm to ambient temperature overnight. The reaction was quenchedwith saturated aqueous NH₄Cl (5.0 mL), extracted with Et₂O, washed withbrine, dried over MgSO₄, filtered and concentrated in vacuo. The crudewas purified using silica gel column chromatography (EtOAc:Heptane,7:93-40:60) to provide the title compound as a colorless oil (78.2 mg,79%) and the minor diastereomer (17.4 mg, 12%). Major diastereomer: ¹HNMR (400 MHz, CDCl₃) δ 4.40 (dt, J=7.6, 3.6 Hz, 1H), 4.15-4.26 (m, 2H),4.02 (q, J=7.0 Hz, 1H), 2.47 (s, 1H), 2.36 (dtd, J=14.0, 7.0, 7.0, 4.1Hz, 1H), 1.63-1.76 (m, 6H), 1.11 (d, J=7.0 Hz, 3H), 0.88 (dd, J=16.6,6.8 Hz, 6H). Minor diastereomer: ¹H NMR (400 MHz, CDCl₃) δ 4.46 (dt,J=8.2, 3.3 Hz, 1H), 4.16-4.29 (m, 2H), 4.04 (q, J=6.6 Hz, 1H), 2.49 (s,1H), 2.26-2.38 (m, 1H), 1.74 (s, 6H), 1.09 (d, J=7.0 Hz, 3H), 0.93 (dd,J=7.0, 4.3 Hz, 6H).

Step 4: (R)-2-(bicyclo[1.1.1]pentan-1-yl)propanoic acid. To a solutionof(R)-3-((R)-2-(bicyclo[1.1.1]pentan-1-yl)propanoyl)-4-isopropyloxazolidin-2-one(78.2 mg, 0.311 mmol) in THF (1.5 mL) at 0° C. was added H₂O₂ (50 wt %,0.10 mL, 1.74 mmol) followed by dropwise addition of LiOH.H₂O (28.7 mg,0.684 mmol) in H₂O (0.5 mL). The ice-water bath was removed and thereaction was allowed to stir at ambient temperature overnight. Thereaction was cooled down to 0° C. and quenched with 1.5 M Na₂SO₃ (1.0mL), diluted with H₂O (3.0 mL). The reaction mixture was extracted withDCM (2×5 mL). The remaining aqueous layer was acidified with 1.0 N HCland extracted with EtOAc (3×10 mL). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated in vacuoto provide the title compound (43.1 mg, 99%). The product was useddirectly without further purification. [α]_(D) ²⁵=−15.9 (c=0.42, EtOH).¹H NMR (400 MHz, CDCl₃) δ 2.60 (q, J=7.0 Hz, 1H), 2.51 (s, 1H), 1.75 (s,6H), 1.11 (d, J=7.0 Hz, 3H).

Step 5:(R)—N-(3-(1-(2-(bicyclo[1.1.1]pentan-1-yl)propanoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-cyanobenzamide.3-Cyano-N-(1,4-dimethyl-3-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamidehydrochloride (60 mg, 0.13 mmol) treated with DMF (0.5 mL), DIPEA (0.24mL, 1.34 mmol), HATU (62 mg, 0.16 mmol), and(R)-2-(bicyclo[1.1.1]pentan-1-yl)acetic acid (22.6 mg, 0.16 mmol). Themixture was then stirred at room temperature for 1 hr. The mixture wasconcentrated and the residue was purified by silica gel columnchromatography (EtOAc:heptane, 60:40-100:0) to afford the title compound(55.3 mg, 83%) as a white solid: LC/MS [M+H]=496.2; Chiral LC: Rt=8.42min (Method D). ¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.30-8.39 (m,1H), 8.15 (d, J=1.9 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.78 (t, J=8.0 Hz,1H), 7.26 (d, J=6.6 Hz, 1H), 4.76 (d, J=14.1 Hz, 1H), 4.25 (d, J=12.9Hz, 1H), 3.84 (d, J=5.1 Hz, 3H), 3.40-3.25 (m, 2H), 3.14 (dd, J=16.0,6.6 Hz, 1H), 2.82 (d, J=15.2 Hz, 1H), 2.68 (s, 3H), 2.50 (d, J=10.9 Hz,1H), 2.07-2.25 (m, 2H), 1.72-1.85 (m, 6H), 1.50-1.72 (m, 2H), 1.09 (dd,J=6.6, 3.9 Hz, 3H).

Example 51 Preparation of(R)-3-cyano-N-(3-(1-(2-cyclopentylpropanoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1: (R)-3-(2-cyclopentylacetyl)-4-isopropyloxazolidin-2-one. To asolution of (R)-benzyl oxazolidinone (2.0 g, 10 mmol) in THF (55 mL) at−78° C. was added dropwise n-BuLi (2.5 M in hexanes, 4.92 mL, 12.3mmol). The resulting solution was allowed to stir at the sametemperature for 1 h, then cyclopentyl acetyl chloride (1.86 g, 12.3mmol) was added. The reaction turned pale yellow rapidly and was allowedto stir at −78° C. for 1 h. The reaction was quenched with sat. NaHCO₃solution, extracted with EtOAc, dried over Na₂SO₄, filtered andconcentrated to afford the title compound (3.20 g, 99%) as a pale yellowoil that solidified on standing. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.28 (m,3H), 7.26-7.16 (m, 2H), 4.74-4.64 (m, 1H), 4.24-4.12 (m, 2H), 3.32 (dd,J=13, 3 Hz, 1H), 3.04 (dd, J=17, 7 Hz, 1H), 2.92 (dd, J=17, 7 Hz, 1H),2.77 (dd, J=14, 10 Hz, 1H), 2.41-2.28 (m, 1H), 1.95-1.84 (m, 2H),1.72-1.56 (m, 4H), 1.30-1.15 (m, 2H).

Step 2: (R)-3-((R)-2-cyclopentylpropanoyl)-4-isopropyloxazolidin-2-one.To a colorless solution of(R)-3-(2-cyclopentylacetyl)-4-isopropyloxazolidin-2-one (3250 mg, 11.34mmol) in THF (50 mL) at −78° C. was added dropwise LDA (2.0 M, 6.50 mL,13.0 mmol). The resulting yellow solution was allowed to stir at thesame temperature for 1 h. Mel (3.55 mL, 56.6 mmol) was added and thereaction was allowed to warm to 0° C. over 1 h and allowed to stir at 0°C. for 3 h. The reaction was quenched with sat. NH₄Cl and extracted withEtOAc. The combined organic extracts were washed with sat. NaHCO₃ andbrine, dried over magnesium sulfate, filtered and concentrated in vacuoto afford a white solid. The crude product was purified by silica gelcolumn chromatography twice (EtOAc:Heptane, 5:95-60:40 then 5:95-50:50).The product was recrystallized from n-heptane to provide the titlecompound (680 mg, 20%) as colorless crystalline needles. ¹H NMR (400MHz, CDCl₃) δ 7.40-7.17 (m, 5H), 4.69 (ddt, J=10, 7, 3 Hz, 1H),4.25-4.11 (m, 2H), 3.63 (dg, J=9, 7 Hz, 1H), 3.28 (dd, J=14, 3 Hz, 1H),2.78 (dd, J=13, 9 Hz, 1H), 2.21-2.08 (m, 1H), 1.90-1.73 (m, 2H),1.71-1.48 (m, 4H), 1.30-1.17 (m, 4H), 1.11 (ddd, J=12.0, 5.0, 4.0 Hz,1H).

Step 3: (R)-2-cyclopentylpropanoic acid. To a solution of(R)-3-((R)-2-cyclopentylpropanoyl)-4-isopropyloxazolidin-2-one (680 mg,2.26 mmol) in THF/H₂O (v/v=1/1, 12 mL) at room temperature was addedLiOH.H₂O (142 mg, 3.38 mmol) followed by H₂O₂ (237 mL, 4.17 mmol, 50 wt%). The resulting solution was allowed to stir at room temperatureovernight. The reaction was quenched with 1.0 M KHSO₄ (8 mL) andextracted with EtOAc (3×). The combined organic extracts were washedwith brine and dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by silica gel column chromatography (EtOAc:Heptane,7:93-50:50) to afford the title compound (285 mg, 89%) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 2.29 (dq, J=9, 7 Hz, 1H), 2.07-1.95 (m,1H), 1.87-1.76 (m, 2H), 1.69-1.51 (m, 4H), 1.31-1.24 (m, 1H), 1.24-1.15(m, 4H).

Step 4:(R)-3-cyano-N-(3-(1-(2-cyclopentylpropanoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.3-Cyano-N-(1,4-dimethyl-3-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamidehydrochloride (60 mg, 0.13 mmol) was treated with DMF (0.5 mL), DIPEA(0.24 mL, 1.34 mmol), HATU (62 mg, 0.16 mmol), and(R)-2-cyclopentylpropanoic acid (22.9 mg, 0.16 mmol). The reactionmixture was then stirred at room temperature for 48 hr. The mixture wasconcentrated and purified by silica gel column chromatography (20:1,EtOAc:MeOH) to afford the title compound (65 mg, 97%). LC/MS[M+H]=498.2. Chiral LC: rt=8.74 min (Method C); ¹H NMR (CDCl₃) δ8.45-8.21 (m, 4H), 7.84 (d, J=7 Hz, 1H), 7.63 (t, J=8 Hz, 1H), 6.90 (d,J=22 Hz, 1H), 4.76 (t, J=12 Hz, 1H), 4.14 (d, J=13 Hz, 1H), 3.76 (s,3H), 3.22-3.17 (m, 2H), 2.68-2.57 (m, 5H), 2.11-1.02 (m, 16H).

Example 52 Preparation of3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide

The title compound was prepared by procedures analogous to thosedescribed for Example 5 starting from tert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate(prepared as described in Example 32) and utilizing cyclopentanecarbonylchloride in Step 3. The resulting(4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl)(cyclopentyl)methanoneintermediate in Step 4 was coupled with 3-cyano-5-methoxybenzoic acid inthe presence of 2-chloromethylpyridinium iodide and DIPEA in THF. LC/MS[M+H]=500. 1; ¹H NMR (500 MHz, CDCl₃) δ 8.23 (s, 1H), 7.97 (br s, 1H),7.82 (s, 1H), 7.77 (br s, 1H), 7.34 (br s, 1H), 6.93 (s, 1H), 4.78 (brd, J=12.9 Hz, 1H), 4.11 (br d, J=13.2 Hz, 1H), 3.92 (s, 3H), 3.82 (s,3H), 3.26-3.12 (m, 2H), 2.94 (quintet, J=8 Hz, 2H), 2.67 (dt, J=1.8,13.0 Hz, 1H), 2.59 (s, 3H), 2.12-2.06 (m, 1H), 2.04-1.98 (m, 1H),1.90-1.37 (m, 10H).

Example 53 Preparation of3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-hydroxybenzamide

To a solution of3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide(prepared as described in Example 52, 100 mg, 0.200 mmol) in DCM (10 mL)was added boron tribromide (1.5 mL) at −60° C. A precipitate formed fromthe clear brown solution, and the resulting mixture was stirred at 15°C. for 12 h. The mixture was evaporated and the residue was brought upin H₂O (20 mL) and extracted with EtOAc (15 mL) twice. The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated to afford the title compound (96 mg, 99%) as a solid. LC/MS[M+H]=486.1; ¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1H), 8.06 (s, 1H), 7.74(s, 1H), 7.63 (s, 1H), 7.35 (s, 1H), 7.26 (s, 1H), 4.57-4.54 (m, 1H),4.11-4.08 (m, 1H), 3.75 (s, 3H), 3.21-2.68 (m, 4H), 2.50 (s, 3H),2.02-1.99 (m, 2H), 1.77-1.44 (m, 10H).

Examples 54-56

The following Examples 54-56 were prepared analogous to Example 53employing the corresponding methyl ether.

Ex. Structure Name/Characterization 54

(R)-3-cyano-5-hydroxy-N-(1-methyl-4-(trifluoromethyl)-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + Na] = 578.3. ChiralSFC: Rt = 2.376 min (Method N). ¹H NMR (400 MHz CDCl₃) δ 9.30 (s, 1H),9.11 (s, 1H), 8.46- 8.30 (m, 2H), 7.66-7.62 (m, 2H), 7.22-7.19 (m, 2H),4.88-4.83 (m, 1H), 4.25-4.22 (m, 1H), 3.85-3.77 (m, 3H), 3.21-3.11 (m,2H), 2.80-2.65 (m, 2H), 2.04-1.90 (m, 2H), 1.53-0.99 (m, 15H). 55

3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-hydroxybenzamide. LC/MS [M + H] = 540.3; ¹H NMR (400 MHz, DMSO-d₆)δ 10.50 (s, 1H), 8.29 (s, 1H), 7.86- 7.84 (m, 2H), 7.67-7.66 (m, 1H),7.89 (s, 1H), 4.57- 4.42 (m, 1H), 4.23-4.05 (m, 1H), 3.85 (s, 3H), 3.07-3.01 (m, 3H), 2.57-2.52 (m, 1H), 1.95-1.40 (m, 12H). 56

(R)-3-cyano-N-(1,4-dimethyl-3-(1-(2,3,3-trimethylbutanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-hydroxybenzamide. LC/MS [M + H] = 502.3; Chiral LC: Rt= 3.23 min (Method U); ¹H NMR (400 MHz, CDCl₃) δ 10.16 (br s, 1H), 8.77(s, 1H), 8.16- 8.06 (m, 1H), 7.61-7.51 (m, 1H), 7.07-7.01 (m, 1H), 6.88-6.85 (m, 1H), 4.83-4.72 (m, 1H), 4.31-4.22 (m, 1H), 3.70- 3.60 (m, 3H),3.23-3.09 (m, 2H), 3.77-3.62 (m, 2H), 2.49 (s, 3H), 2.10-1.20 (m, 5H),1.14-1.09 (m, 3H), 1.00- 0.98 (m, 9H).

Example 57 Preparation of3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(2-methoxyethoxy)benzamide

To a mixture of3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-hydroxybenzamideand K₂CO₃ (85.4 mg, 0.618 mmol) in DMF (8 mL) was added1-bromo-2-methoxyethane (57.2 mg, 0.412 mmol). The mixture was stirredat 30° C. for 16 h and then at 50° C. for 12 h. Water (15 mL) was addedand the mixture was extracted with EtOAc (15 mL) twice. The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The crude product was purified by silica gel columnchromatography (MeOH:DCM, 0:100-10:90) and then by preparative HPLC(Phenomenex Gemini C18, 250 mm×21.2 mm×8 μm, 27-47% MeCN (0.05% Ammonia)in water (0.05% Ammonia)). Lyophilization provided the title compound(21 mg, 18%) as a white solid. LC/MS [M+H]=544.1; ¹H NMR (400 MHz,CDCl₃) δ 8.44 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.33(s, 1H), 6.80 (s, 1H), 4.72-4.70 (m, 1H), 4.20 (s, 2H), 4.10-4.07 (m,1H), 3.79-3.77 (m, 5H), 3.17 (s, 3H), 2.95-2.91 (m, 1H), 2.63-2.55 (m,4H), 2.07-2.04 (m, 1H), 1.94-1.91 (m, 1H), 1.82 (br s, 4H), 1.72-1.24(m, 10H).

Example 58 Preparation of(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide

Step 1:1,4-dimethyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine.A microwave vial was charged with3-iodo-1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (prepared asdescribed in Example 32, 0.5 g, 1.57 mmol) and Xantphos (0.147 g, 0.31mmol). Toluene (2 mL) was introduced into the vial and the suspensionwas degassed with argon for 30 min.4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (0.8 g, 6.31 mmol) and TEA (1.13mL, 7.9 mmol) was added to the mixture and was further degassed for 2min. Finally, Pd(OAc)₂ (35.8 mg, 0.16 mmol) was added to the suspensionand the vial was sealed using a Teflon cap. The reaction was heated to120° C. under microwave irradiation for 30 min. After cooling, thereaction was filtered through a pad of Celite® and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (EtOAc:hexane, 1:4) to provide the title compound (0.4 g,80%). LC/MS [M+H]=318.05; ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 7.82(s, 1H), 3.90 (s, 3H), 3.04 (s, 3H), 1.36 (s, 12H).

Step 2a: tert-butyl2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.To a RB flask charged with tert-butyl2,2-dimethyl-4-oxopiperidine-1-carboxylate (7.76 g, 34.1 mmol) in dryTHF (130 mL) was added slowly dropwise at −70° C. a solution of sodiumbistrimethyldisilazide (7.51 g 41.0 mmol) in THF (41 mL). Upon completeaddition, a solution of N-phenyltriflamide (16.1 g, 41.0 mmol) in THF(10 mL) was added and the mixture was allowed to warm to roomtemperature over the course of 12 h. The reaction mixture was thenconcentrated and brought up in EtOAc:heptane (85:15, 100 mL) and washedtwice with water. The combined organics were collected and concentratedto give 12.0 g (98%) of the titled compound as a yellow oil. ¹HNMR (400MHz, CDCl₃) δ 5.78 (t, J=3.5 Hz, 1H), 4.08 (q, J=2.7 Hz, 2H), 2.40 (brs, 2H), 1.37-1.58 (m, 14H).

Step 2b: tert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate.To a solution of tert-butyl2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(2.9 g, 8.09 mmol) in a mixed solvent of dioxane/H₂O (70 mL, 9/1) wasadded1,4-dimethyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(2.33 g, 7.35 mmol,) and K₃PO₄ (3.44 g, 16.2 mmol, 2.2 eq). Pd(PPh₃)₄(850 mg, 0.736 mmol, 0.1 eq) was added and the reaction was degassedusing nitrogen three times. The reaction mixture was heated to 60° C.for 12 hr. The reaction mixture was cooled to room temperature andfiltered through a pad of Celite®. The filtrate were concentrated andthe residue was purified by silica gel column chromatography (PE:EtOAc,100:0-89:11) to give the title compound (2.50 g, 77%) as a yellow solid.LCMS [M+H] 401.1; ¹HNMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 7.12 (s, 1H),5.97-5.94 (m, 2H), 4.09-4.80 (m, 2H), 3.89 (s, 3H), 2.83 (s, 3H), 2.46(s, 2H), 1.55-1.49 (m, 15H).

Step 3:3-(2,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine.An excess of 4N HCl/dioxane (50 mL) was added to a solution oftert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate(2.50 g, 6.26 mmol) in dioxane (1 mL) and this mixture was allowed tostir at room temperature for 1 hr. The mixture was concentrated underreduced pressure to afford the hydrochloride salt of the title compound(1.87 g, 99.8%) as a yellow solid. LCMS [M+H]=301.2.

Step 4:cyclopentyl(4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethyl-3,6-dihydropyridin-1(2H)-yl)methanone.DIPEA (540 mg, 4.18 mmol), HATU (691 mg, 1.67 mmol) and cyclopentanecarboxylic acid (286 mg, 2.51 mmol) were added to a mixture of3-(2,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridinehydrochloride (250 mg, 0.83 mmol) in dry DCM (10 mL) and the mixture wasallowed to stir at room temperature for 1 hr. The mixture was thenpoured into water and extracted with ethyl acetate (10 mL). The organiclayer was concentrated and the residue was purified by silica gel columnchromatography (PE:EtOAc, 100:0-55:45) to afford the title compound (310mg, 83%) as a yellow solid. LCMS [M+H]=397.1.

Step 5:(4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidin-1-yl)(cyclopentyl)methanone.To a solution ofcyclopentyl(4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethyl-3,6-dihydropyridin-1(2H)-yl)methanone(1.55 g, 3.92 mmol) in TEA (1.09 mL, 7.84 mmol) was added a mixedsolvent of EtOH/DCM (90 mL/30 mL), and the mixture was degassed andpurged with hydrogen three times. PtO₂ (178 mg, 0.784 mmol) was addedand the mixture was stirred under a hydrogen atmosphere (55 psi) for 24h. The mixture was filtered through a pad of Celite® and washed throughwith MeOH (3×50 mL). The filtrate was concentrated and the crude productwas purified by silica gel column chromatography (DCM:MeOH, 100:0-99:1)to give the title compound (1.45 g, 99.7%) as a red solid. LCMS[M+H]=369.0; ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 6.88 (s, 1H),4.15-4.09 (m, 1H), 3.84-3.75 (m, 4H), 3.39-3.32 (m, 2H), 2.51 (s, 3H),2.07-2.09 (m, 1H), 1.84 (s, 1H), 1.81-1.73 (m, 8H), 1.62-1.51 (m, 6H).

Step 6:rac-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide.TEA (0.170 mL, 1.22 mmol) was added to a solution of(4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidin-1-yl)(cyclopentyl)methanone(150 mg, 0.41 mmol) in dry DCM (25 mL). A solution of3-cyano-5-methoxybenzoyl chloride (79.6 mg, 0.407 mmol) in dry DCM (5mL) was then slowly added at 0° C. The mixture was allowed to stir atambient temperature for 3 hr. The reaction mixture was quenched withwater (10 mL) and the organic layer was separated, dried over Na₂SO₄,and concentrated. The residue was purified by silica gel columnchromatography (DCM:MeOH, 100:0-96:4) to afford the title compound (165mg, 76.8%).

Step 7:(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide.rac-3-Cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamidewas resolved by preparative chiral HPLC (Chiralpak AD, 250×30 mm, 5 μm;30% IPA+NH₃.H₂O; 60 mL/min) by collecting the first eluting isomer toafford the title compound. LC/MS [M+Na]=550.0; Chiral LC: Rt=1.96 min(Method E); [α]^(D) ₂₀=+28.31 (c=0.0034 g/mL, DCM); ¹H NMR (400 MHz,CDCl₃) δ 8.32-8.08 (m, 2H), 7.64 (br. s., 1H), 7.16-6.89 (m, 2H), 4.04(s, 3H), 3.92-3.72 (m, 4H), 3.50-3.21 (m, 2H), 2.91 (t, J=7.8 Hz, 1H),2.62 (s, 2H), 2.17 (br. s., 1H), 1.95-1.68 (m, 8H), 1.37-1.63 (m, 10H).Absolute stereochemistry has been assigned based on potency comparisonof enantiomers and the corresponding configuration of Example 60determined through a co-crystal X-ray structure.

Examples 59-63

The following Examples 59-63 were prepared analogous to Example 58employing the appropriate carboxylic acid or carboxylic acid chloridecoupling partners in Steps 4 and 6. Absolute stereochemistry has beenassigned based on potency comparison of enantiomers and thecorresponding configuration of Example 60 determined through aco-crystal X-ray structure.

Ex. Structure Name/Characterization 59

(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methylbenzamide. LC/MS [M + Na] = 534.1; Chiral LC: Rt= 2.79 min (Method E); [α]^(D) ₂₀ = +18.6 (c = 0.0023 g/mL, DCM); ¹H NMR(400 MHz, CDCl₃) δ 8.50(J = 17.6 Hz, 2H), 8.08 (d, J = 7.5 Hz, 1H), 7.65(s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 3.85 (s, 4H), 3.20-3.49 (m, 1H), 2.91 (t, J = 7.5 Hz, 1H), 2.66 (s, 6H), 1.69- 1.93 (m,7H), 1.32-1.64 (m, 12H). 60

(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + Na] = 550.0; Chiral LC:Rt = 6.72 min (Method E); [α]^(D) ₂₀ = +22.4 (c = 0.0039 g/mL, DCM); ¹HNMR (400 MHz, CDCl₃) δ 8.08-8.32, (m, 2 H), 7.64 (br. s., 1 H),6.89-7.16 (m, 2 H), 4.04 (s, 3 H), 3.72-3.92 (m, 4 H), 3.21-3.50 (m, 2H), 2.91 (t, J = 7.78 Hz, 1 H) 2.62 (s, 2 H) 2.17 (br. s., 1 H)1.68-1.95 (m, 8 H), 1.37-1.63 (m, 10 H) 61

(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorobenzamide. LC/MS [M + Na] = 538.1; Chiral LC: Rt= 5.97 min (Method F); [α]^(D) ₂₀ = −41.6 (c = 0.0036 g/mL, DCM); ¹H NMR(400 MHz, CDCl₃) δ 8.34-8.07 (m, 3H), 7.71 (br. s., 1H), 7.39 (t, J =8.5 Hz, 1H), 7.01 (s, 1H), 3.85 (s, 4H), 3.52-3.25 (m, 2H), 2.82-3.17(m, 2H), 2.62 (s, 3H), 2.17 (br. s., 1H), 1.93-1.70 (m, 6H), 1.39- 1.65(m, 10H). 62

(R)-3-chloro-N-(3-(1-isobutyryl-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5- methoxybenzamide.LC/MS [M + H] = 511.3; Chiral LC: Rt = 1.55 min (Method Y); ¹H NMR (400MHz, CDCl₃) δ 8.21 (s, 1H), 7.98 (s, 1H), 7.48 (s, 1H), 7.39 (s, 1H),7.07 (s, 1H), 6.98 (s, 1H), 3.86-3.77 (m, 7H), 3.45- 3.30 (m, 2H),2.85-2.78 (m, 1H), 2.59 (s, 3H), 2.20- 2.15 (m, 1H), 1.90-1.65 (m, 3H),1.60 (s, 3H), 1.50 (s, 3H), 1.15-1.07 (m, 6H). 63

(R)-3-chloro-N-(3-(1-(cyclopentane-carbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide. LC/MS [M + Na] = 537.3; Chiral LC:Rt = 1.43 min (Method B); ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.84(s, 1H), 7.48 (s, 1H), 7.39 (s, 1H), 7.08 (s, 1H), 6.99 (s, 1H),3.87-3.83 (m, 7H), 3.42-3.25 (m, 2H), 2.92-2.85 (m, 1H), 2.61 (s, 3H),2.25-2.15 (m, 1H), 1.90-1.45 (m, 17H).

Example 64 Preparation of(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-hydroxybenzamide

BBr₃ (800 mg, 3.0 mmol, 0.3 mL) was added to a solution of(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide(prepared in Example 58, 70 mg, 0.133 mmol) in DCM (5.0 mL) at −60° C.The resulting mixture was stirred at −65° C. for 2 h. Additional BBr₃(2700 mg, 11.0 mmol, 1.0 mL) was added at −60° C. After 20 min, theresulting mixture was stirred at 18° C. for 30 min. The mixture wascooled to −60° C. and then water (12 mL) was added. The mixture wasconcentrated and the crude product was purified by silica gel columnchromatography (DCM/MeOH, 100/0-87/13). The product was dissolved inMeOH (8 mL) and water (25 mL). The resulting precipitate was collectedby filtration and again purified by silica gel column chromatography(DCM/MeOH, 100/0-82/18) to afford the title compound (65 mg, 73%). LC/MS[M+H]=514.2. Chiral SFC: Rt=1.422 min (Method M). ¹H NMR (400 MHz CD₃OD)δ 8.11 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.31 (s, 1H), 7.27 (s, 1H),3.94-3.82 (m, 4H), 3.53-3.47 (m, 2H), 3.07-3.03 (m, 1H), 2.64 (s, 3H),2.26-2.21 (m, 1H), 1.91-1.54 (m, 19H).

Example 65 Preparation of(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1:1-methyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine.4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (2760 mg, 21.6 mmol), Pd(OAc)₂(120 mg, 0.54 mmol), X-PHOS (514 mg, 1.08 mmol), and TEA (2760 mg) wasadded to a solution of3-iodo-1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(prepared as described in Example 1, 2000 mg, 5.4 mmol) in toluene (40mL). The mixture was heated to 120° C. for 0.5 h under N₂. The reactionmixture was filtered and concentrated in vacuo. The residue was purifiedby silica gel column chromatography (PE:EtOAc, 3:1) to afford the titlecompound (1350 mg, 67.5%) as a pale yellow solid. LC/MS [M+H]=372.0; ¹HNMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 7.88 (s, 1H), 3.95 (s, 3H), 1.37(s, 12H).

Step 2: tert-butyl6,6-dimethyl-4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate:Under N₂, a solution of1-methyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(2500 mg, 6.74 mmol), tert-butyl6,6-dimethyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(2410 mg, 6.74 mmol), Pd(PPh₃)₄ (778 mg, 0.674 mmol) and K₂CO₃ (3720 mg,26.9 mmol) in dioxane/H₂O (100 mL/10 mL) was heated to 70° C. andstirred for 15 hr. The reaction mixture was extracted with DCM (500 mL).The organic layer washed with brine (200 mL), dried over Na₂SO₄, andconcentrated. The residue was purified by silica gel columnchromatography (DCM:MeOH, 100:1-30:1) to afford the title compound (1700mg, 55.5%) as a yellow solid. LC/MS [M-Boc]=354.8.

Step 3: (R)-tert-butyl4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate:A solution of tert-butyl6,6-dimethyl-4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate(4500 mg, 9.9 mmol) in EtOH (300 mL) and DCM (30 mL) was degassed andpurged with hydrogen three times. Pd(OH)₂ (200 mg) was added and themixture was stirred under hydrogen (55 psi) at 50° C. for 45 h. Thereaction was then filtered through a pad of Celite® and washed with MeOH(3×30 mL). The filtrate was then concentrated and purified by silica gelcolumn chromatography (PE:EtOAc, 3:1). The resulting solid was resolvedby chiral preparatory LC (Chiralcel OJ-R 150×4.6 mm I.D., 5 μm, Water(0.069% TFA):Acetonitrile, 10% to 80%, Flow rate: 0.8 mL/min). Isolationof the first eluting peak afforded (S)-tert-butyl4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate.Isolation of the second eluting peak afforded the title compound (540mg) as a pink solid. LC/MS [M+H]=427.0; ¹H NMR (CDCl₃) δ 7.91 (1H, s),7.09 (1H, s), 4.13 (2H, s, br), 4.08-4.05 (1H, m), 3.81 (3H, s),3.25-3.17 (1H, m), 3.17-3.08 (1H, m), 1.98 (1H, d, br, J=4.0 Hz),1.77-1.71 (1H, m), 1.65-1.45 (8H, m), 1.36 (9H, s). Absolutestereochemistry of the products have been assigned based on potencycomparison of the enantiomers obtained in step 6 and the correspondingconfiguration of Example 60 determined through a co-crystal X-raystructure.

Step 4: (R)-tert-butyl4-(5-(3-cyanobenzamido)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate:To a stirred solution of (R)-tert-butyl4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate(100 mg, 0.234 mmol) in THF (10 mL) was added 3-cyanobenzoic acid (42mg, 0.281 mmol), 2-chloromethylpyridinium iodide (120 mg, 0.469 mmol)and DIPEA (0.1 mL) at 55° C. The reaction mixture was allowed to stirfor 15 hr. Water was added, and then the mixture was extracted with DCM.The organic layer was separated, dried over Na₂SO₄, and concentrated.The crude product was purified by silica gel column chromatography(PE:EA, 2:1) to give the title compound (100 mg, 76.8%) as a whitesolid. LC/MS [M+H]=556.0.

Step 5:(R)-3-cyano-N-(3-(2,2-dimethylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide:(R)-tert-butyl4-(5-(3-cyanobenzamido)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate(100 mg, 0.18 mmol) was added to a solution of HCl in dioxane (4 M, 5mL) at room temperature. The mixture was stirred for 15 hr and thenconcentrated to give the hydrochloride salt for the title compound (80mg, 90%) as a yellow solid. LC/MS [M+H]=456.0.

Step 6:(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide:To a solution of(R)-3-cyano-N-(3-(2,2-dimethylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide(80 mg, 0.16 mmol) and TEA (0.1 mL) in DCM (10 mL), was addedcyclopentanecarbonyl chloride (22 mg, 0.16 mmol) at room temperature.The resulting mixture was then allowed to stir for 15 hr. The reactionmixture was concentrated and then purified by preparative HPLC (AgelaDurashell C18, 250×21.2 mm×5 μm, 45% MeCN/water (0.225% FA) to 65% MeCNin water (0.225% FA)). The resulting product was further purified bychiral preparative LC (Chiralcel OJ-R 150×4.6 mm I.D., 5 um, water(0.069% TFA):Acetonitrile, 10% to 80%, Flow rate: 0.8 mL/min, rt=4.46min) to afford the title compound (32.7 mg, 36%) as a white solid. LC/MS[M+H]=552.1; ¹H NMR (CDCl₃) δ 8.56 (1H, s), 8.25 (1H, s), 8.17 (1H, d,J=8.0 Hz), 8.10 (1H, s), 7.88 (1H, d, J=7.6 Hz), 7.67 (1H, t, J=8.0 Hz),7.30 (1H, s), 3.93 (3H, s), 3.88-3.82 (1H, m), 3.34-3.28 (2H, m),2.93-2.89 (1H, m), 2.14-2.10 (1H, m), 1.87-1.57 (17H, m). Absolutestereochemistry has been assigned based on potency comparison ofenantiomers and the corresponding configuration of Example 60 determinedthrough a co-crystal X-ray structure.

Examples 66-67

The following Examples 66-67 were prepared analogous to Example 64employing the appropriate carboxylic acid or carboxylic acid chloridecoupling reagents in Steps 4 and 6. Absolute stereochemistry has beenassigned based on potency comparison of enantiomers and thecorresponding configuration of Example 44 was determined through aco-crystal X-ray structure.

Ex. Structure Name/Characterization 66

(R)-3-cyano-N-(3-(1-isobutyryl-2,2-dimethylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 526.1; ¹H NMR (400 MHz, CDCl₃)δ 8.55 (s, 1H), 8.25 (s, 1H), 8.18-8.16 (m, 2H), 7.88-7.86 (m, 1H),7.68-7.64 (m, 1H), 7.30-7.27 (m, 1H), 3.92 (s, 3H), 3.84-3.80 (m, 1H),3.34-3.28 (m, 2H), 2.82-2.79 (m, 1H), 2.13-2.11 (m, 1H), 1.75-1.08 (m,13H). 67

(R)-3-cyano-N-(3-(1-isobutyryl-2,2-dimethylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] = 556.1; ¹H NMR (400MHz, CDCl₃) δ 8.49 (s, 1H), 8.19- 8.14 (m, 3H), 7.27-7.25 (m, 1H),7.08-7.06 (m, 1H), 4.01 (s, 3H), 3.89 (s, 3H), 3.81-3.80 (m, 1H), 3.31-3.22 (m, 2H), 2.80-2.77 (m, 1H), 2.10-2.08 (m, 1H), 1.72-1.05 (m, 15H),

Example 68 Preparation of3-cyano-N-(3-((R)-2,2-dimethyl-1-((R)-2,3,3-trimethylbutanoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1: tert-butyl4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate.This reaction was run in six parallel batches. To a Parr hydrogenationvessel charged with tert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate(prepared as described in Example 58, 850 mg, 2.12 mmol) was addedPd(OH)₂ (29.8 mg, 0.21 mmol), DCM (30 mL), and methanol (100 mL),sequentially. The vessel was sealed and its atmosphere was replaced withhydrogen gas (50 psi H₂) and agitated at room temperature for 24 hours.The vessel's atmosphere was then reequilibrated with atmosphericconditions. The reaction mixture was filtered through a pad of Celite®and rinsed with methanol (10 mL). The filtrates were then concentratedunder reduced pressure and each crude residue was combined with allprevious batches totaling (3.6 g, 70% for the combined 6 batches). Thecrude residue was then purified by SFC chiral separation (Chiralcel OJ,300×50 mm, 10 μm, 35% MeOH+NH₄OH, 200 mL/min). Peak 1 (1.1 g recoveredafter concentration) corresponded to the (R)-enantiomer which usingMethod K eluted at 8.15 min. Peak 2 (1.2 g recovered afterconcentration) corresponded to the (S)-enantiomer which using Method Keluted at 8.35 mins. The absolute configuration of the second elutingenantiomer was established by X-ray crystallography methods as describedin Example 108. LC/MS [M+H]=373.1; ¹H NMR (400 MHz, CDCl₃) δ 7.89 (br s,1H), 6.86 (s, 1H), 4.04-4.01 (m, 1H); 3.77 (s, 3H), 3.37-3.17 (m, 4H),2.50 (s, 3H), 2.11-2.08 (m, 1H), 1.86-1.83 (m, 1H), 1.70-1.42 (m, 17H).

Step 2: tert-butyl(R)-4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate.To a vessel charged withtert-butyl-(R)-4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate(500 mg, 1.45 mmol), was sequentially added at room temperature3-cyanobenzoic acid (214 mg, 1.45 mmol), 2-chloro-1-methylpyridiniumiodide (370 mg, 1.45 mmol), DIPEA (750 mg, 5.81 mmol), and THF (15 mL).The mixture was warmed to 70° C. and allowed to stir for 3 hours. Themixture was then concentrated under reduced pressure to give a cruderesidue which was dissolved in ethyl acetate (30 mL), then washed withwater (30 mL), brine (30 mL). The organic layer was dried over Na₂SO₄,and concentrated to give the title compound (640 mg, 93.1%) as a lightyellow solid.

Step 3:(R)-3-cyano-N-(3-(2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamidehydrochloride. To a vessel charged with crude tert-butyl(R)-4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate(80 mg, 0.16 mmol) was added EtOAc (2 mL) and HCl in EtOAc (4 M, 2 mL)dropwise at room temperature. The mixture was stirred at roomtemperature for an additional 2 hours. The reaction mixture was thenconcentrated to give the hydrochloride salt of the title compound (80mg, 120% crude yield) as a light yellow solid. LC/MS [M+H]=373.1.

Step 4:3-cyano-N-(3-((R)-2,2-dimethyl-1-((R)-2,3,3-trimethylbutanoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.To a stirred solution of(R)-3-cyano-N-(3-(2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamidehydrochloride (100 mg, 0.232 mmol) in DCM (4 mL) was added triethylamine(0.5 mL, 0.9 mmol) and (−)-(R)-2,3,3-trimethylbutanoic acid (Kido, M.;Sugiyama, S.; Satoh, T. Tetrahedron: Assym 2007, 18, 1934-47.) (100 mg,0.67 mmol) at room temperature. The mixture was then stirred for 1 hour,then the solvent was removed under reduced pressure, and the residue waspurified by HPLC. After lyophilization, the title compound (20 mg, 16%)was obtained as a white solid. LC/MS [M+H]=514.1; ¹H NMR (400 MHz,CDCl₃) δ 8.38-8.10 (m, 3H), 7.87 (d, J=7.0 Hz, 1H), 7.80-7.55 (m, 2H),7.01 (br. s., 1H), 3.84 (br. s., 4H), 3.42 (br. s., 2H), 2.62 (br. s.,4H), 2.23 (br. s., 1H), 1.94-1.74 (m, 2H), 1.56 (m, 6H), 1.17-0.78 (m,13H); Chiral SFC: Rt=5.28 min (Method L).

Examples 69-76

The following Examples 69-76 were prepared analogous to Example 68,employing the appropriate carboxylic acid or carboxylic acid chloridecoupling reagents in Steps 2 and 4. Absolute configuration is based on asingle crystal X-ray structure of tert-butyl(S)-4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylateintermediate in Step 3 of Example 77 (see Example 108).

Ex. Structure Name/Characterization 69

3-cyano-N-(3-((R)-2,2-dimethyl-1-((R)-2,3,3-trimethylbutanoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] = 544.2;¹H NMR (400 MHz, CDCl₃) δ 8.30-8.12 (m, 3H), 7.76 (br. s., 1H), 7.10 (d,J = 9.1 Hz, 1H), 6.99 (s, 1H), 4.03 (s, 3H), 3.88-3.69 (m, 4H),3.48-3.36 (m, 2H), 2.61 (s, 4H), 2.31-2.12 (m, 1H), 1.89-1.78 (m, 2H),1.41-1.72 (m, 7H), 1.09 (d, J = 6.5 Hz, 3H), 1.00 (s, 9H). 70

(R)-3-cyano-N-(3-(1-isobutyryl-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4- methoxybenzamide.LC/MS [M + H] = 502.1; ¹H NMR (400 MHz, CDCl₃) δ 8.22 (br. s., 3H), 7.95(br. s., 1H), 7.08 (d, J = 9.0 Hz, 1H), 6.99 (s, 1H), 4.02 (s, 3H),3.89-3.69 (m, 4H), 3.51-3.21 (m, 2H), 2.84-2.77 (m, 1H), 2.60 (s, 3H),2.24-2.12 (m, 1H), 1.90-1.68 (m, 3H), 1.60 (s, 3H), 1.48 (s, 3H),1.14-1.08 (m, 6H). 71

(R)-3-cyano-N-(3-(1-(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 498.4; Chiral LC: Rt = 2.58min (Method J); ¹H NMR (CDCl₃) δ 10.05 (1 H, s), 8.65-8.37 (3 H, m),7.84 (1 H, d, J = 7 Hz), 7.66 (s, 1H), 7.08 (s, 1H), 4.07 (s, 3H),3.85-3.82 (m, 1H), 3.49-3.20 (m, 2H), 2.91-2.87 (m, 1H), 2.75 (s, 3H),2.25-2.19 (m, 1H), 1.81-1.38 (m, 17H). 72

(R)-3-cyano-N-(3-(1-isobutyryl-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide. LC/MS [M + H]= 472.2; ¹H NMR (CDCl₃) δ 8.28-8.15 (4 H, m), 7.81 (1 H, d, J = 8 Hz),7.61 (1 H, t, J = 8 Hz), 6.98 (1 H, s), 3.82-3.74 (4 H, m), 3.45- 3.36(1 H, m), 3.29 (1 H, ddd, J = 14, 10, 3 Hz), 2.83- 2.70 (m, 1H), 2.59(s, 3H), 2.22-2.11 (m, 1H), 1.84- 1.61 (m, 3H), 1.57 (s, 3H), 1.46 (s,3H), 1.08 (dd, J = 16, 7 Hz, 6H). 73

3-cyano-N-(3-((R)-2,2-dimethyl-1-((R)-4,4,4-trifluoro-3-hydroxybutanoyl)piperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 542.2; LC: Rt =4.08 min (Method AB); ¹H NMR (CDCl₃) δ 8.35-8.15 (4 H, m), 7.87-7.73 (1H, m), 7.66-7.54 (1 H, m), 6.92 (1 H, s), 4.70 (1 H, s), 4.41- 4.28 (1H, s), 3.82 (3 H, s), 3.74-3.59 (2 H, m), 3.45- 3.17 (2 H, m), 2.54 (3H, s), 2.22-2.08 (1 H, m), 1.82- 0.69 (10 H, m). 74

(R)-3-cyano-N-(3-(1-(2-cyclopentylacetyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 512.3; ¹H NMR (CDCl₃) δ8.26-8.12 (m, 4H), 7.85-7.83 (m, 1H), 7.65-7.61 (m, 1H), 6.99 (s, 1H),3.78 (s, 3H), 3.77- 3.74 (m, 1H), 3.38-3.27 (m, 2H), 2.61 (s, 3H), 2.36-2.18 (m, 4H), 1.81-1.47 (m, 13H), 1.15-1.14 (m, 2H). 75

(R)-3-cyano-N-(3-(1-(2-cyclohexylacetyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 526.4; ¹H NMR (400 MHz, CDCl₃)δ 8.30-8.15 (m, 4 H), 7.86- 7.84 (m, 1H), 7.67-7.63 (m, 1H), 7.00 (s, 1H), 3.84 (s, 3H), 3.81-3.71 (m, 1H) 3.43-3.36 (m, 1H), 3.32-3.23 (m,1H), 2.62 (s, 3H), 2.44-2.11 (m, 4H), 1.89-1.78 (m, 4H), 1.78-1.66 (m,4H), 1.63 (s, 3H), 1.58-1.55 (m, 2H), 1.49 (s, 3H), 1.47-1.42 (m, 1H),1.21-1.09 (m, 2H). 76

(R)-3-cyano-N-(3-(1-(2-cyclobutylacetyl)-2,2-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 498.3. ¹H NMR (400 MHz, CDCl₃)δ 8.33-8.18 (m, 3H), 8.03 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.66 (t, J= 7.8 Hz, 1H), 7.00 (s, 1H), 3.85 (s, 3H), 3.75 (dt, J = 13.6, 5.1 Hz,1H), 3.40 (t, J = 11.12 Hz, 1H), 3.26 (ddd, J = 13.7, 9.9, 3.7 Hz, 1H),2.75-2.62 (m, 1H), 2.63 (s, 3H), 2.56- 2.38 (m, 2H), 2.16 (td, J = 7.5,3.3 Hz, 3H), 1.94-1.73 (m, 3H), 1.75-1.65 (m, 2H), 1.62 (s, 3H),1.52-1.49 (m, 1H), 1.47 (s, 3H), 1.56-1.37 (m, 1H).

Example 77 Preparation of3-cyano-N-(3-((1R,5S,8r)-3-isobutyryl-3-azabicyclo[3.2.1]octan-8-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1: tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. BOCanhydride (5.81 g, 26.6 mmol) and Pearlman's catalyst (1.55 g, 23.2mmol) were successively added to a solution of3-benzyl-3-azabicyclo[3.2.1]octan-8-one obtained from commercial sources(CAS 83507-33-9) (5.0 g, 22.0 mmol) in EtOAc (74 mL) at roomtemperature. The reaction vessel was alternately filled with nitrogenand evacuated (3×) and then filled and evacuated with hydrogen (2×). Themixture was stirred overnight under 100 psi of H₂. The mixture wasfiltered through a pad of Celite® which was washed with ethyl acetate.The filtrate was concentrated and the crude product was purified bysilica gel chromatography (heptane:EtOAc, 0:100-100:0) to provide thetitle compound (4.49 g, 90%) as a solid. LC/MS [M−Me]=211.1. ¹H NMR (400MHz, CDCl₃) δ 4.38 (d, J=14.0 Hz, 1H), 4.20 (d, J=14.0 Hz, 1H), 3.27 (d,J=13.3 Hz, 1H), 3.17 (d, J=13.3 Hz, 1H), 2.24 (d, J=15.6 Hz, 2H),1.76-1.99 (m, 4H), 1.49 (s, 9H).

Step 2: tert-butyl8-(methoxymethylidene)-3-azabicyclo[3.2.1]octane-3-carboxylate.Potassium tert-butoxide (4.47 g, 39.8 mmol) was added portionwise to asuspension of (methoxymethyl)triphenylphosphonium chloride (12.4 g, 36.1mmol) and tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (4.49g, 19.9 mmol) in THF (100 mL) at 0° C. After 45 min, the cold bath wasremoved and the reaction was stirred overnight at room temperature. Thereaction was recooled at 0° C. and a saturated solution of NH₄Cl wasadded until pH=6. After warming to room temperature, the mixture wasdiluted with water and extracted with DCM. The combined organic layerswere washed with brine, dried with Na₂SO₄, filtered and concentrated.The resulting oil was diluted with a small amount of ether and a largevolume of heptane. After vigorous stirring for 1 h, the resulting solidwas filtered off and washed with additional heptane. The filtrate wasconcentrated and the resulting oil was purified by silica gelchromatography (heptane:EtOAc, 100/0-70/30) to provide the titlecompound (4.73 g, 94%). LC/MS [M−Me]=239.1. ¹H NMR (400 MHz, CDCl₃) δ5.86 (s, 1H), 4.02 (t, J=12.1 Hz, 1H), 3.79-3.94 (m, 1H), 3.57 (s, 3H),2.76-3.05 (m, 3H), 2.41 (m, 1H), 1.58-1.65 (m, 4H), 1.47 (br. s., 9H).

Step 3: tert-butyl(8-anti)-formyl-3-azabicyclo[3.2.1]octane-3-carboxylate. Water (0.473mL) followed by para-toluenesulfonic acid monohydrate (2.71 g, 13.8mmol) was added to a solution of tert-butyl8-(methoxymethylidene)-3-azabicyclo[3.2.1]octane-3-carboxylate (3.33 g,13.14 mmol) in acetone (87.6 mL) at 0° C. The mixture was stirred at 0°C. for 2 h and was quenched at the same temperature with a saturatedsolution of NaHCO₃ until pH=8. Acetone was carefully removed undervacuum (bath at 10° C.) and the aqueous layer was extracted with DCM.The combined organic layers were washed with brine, dried with Na₂SO₄,filtered and concentrated to afford a mixture of predominantly undesireddiastereomer (10.09 ppm) versus desired aldehyde (9.62 ppm) in a 3:1ratio. Complete epimerization was obtained after stirring the crudemixture at room temperature in a mixture of DCM (13.1 mL) and DBU (26.3mmol, 3.93 mL). EtOAc (100 mL) was added and DCM was carefullyevaporated (150 mbar, bath 35° C.) leaving most of the EtOAc in theflask. The reaction was then quenched with a saturated solution ofNH₄Cl. The phases were separated and the organic phase was washed with asaturated solution of NH₄Cl followed by brine, dried with Na₂SO₄,filtered and concentrated. The resulting oil was purified by silica gelchromatography (heptane/EtOAc, 100:0-0:100) to afford the title compound(2.41 g, 77%) as a solid. LC/MS [M-Me]=225.0. ¹H NMR (400 MHz, CDCl₃) δppm 9.63 (s, 1H), 4.03 (d, J=13.3 Hz, 1H), 3.88 (d, J=13.3 Hz, 1H), 2.87(m, 2H), 2.50-2.66 (m, 3H), 1.52-1.67 (m, 4H), 1.47 (s, 9H).

Step 4: tert-butyl8-(1-hydroxy-2-nitroethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate.Nitromethane (815 μL, 15.0 mmol) and potassium tert-butoxide (1 M inTHF, 2.0 mL, 2.0 mmol) were successively added to a solution oftert-butyl (8-anti)-formyl-3-azabicyclo[3.2.1]octane-3-carboxylate (2.40g, 10.0 mmol) in a mixture of THF:t-BuOH (1:1, 10 mL). The mixture wasstirred at 0° C. for 1 h, warmed to room temperature and stirredovernight. The reaction was quenched with a saturated solution of NH₄Cl.The phases were separated and the aqueous phase was extracted with DCM.The combined organic phases were dried over Na₂SO₄, filtered andconcentrated under vacuum. After drying the crude residue for 1 h underhigh vacuum, the title compound (3.10 g, 100%) was obtained as a whitesolid and was used for the next step without purification. LC/MS[M−Me]=286.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 4.55 (d, J=13.7 Hz, 1H),4.36-4.45 (m, 1H), 3.77-4.04 (m, 3H), 3.33-3.41 (m, 1H), 2.72-2.91 (m,2H), 2.58-2.68 (m, 1H), 2.46-2.58 (m, 1H), 1.88-2.01 (m, 1H), 1.53-1.82(m, 4H), 1.47 (br. s, 9H).

Step 5: tert-butyl(E)-8-(2-nitrovinyl)-3-azabicyclo[3.2.1]octane-3-carboxylate. TEA (8.56mmol, 1.19 mL) was added to a solution of tert-butyl(8-anti)-(1-hydroxy-2-nitroethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate(1.28 g, 4.28 mmol) in DCM (5.48 mL) at 0° C. Methanesulfonyl chloride(4.71 mmol, 0.367 mL) was then slowly added. After stirring for 10 minat 0° C., the mixture was quenched with water. The layers were separatedand the organic phase was washed with a saturated aqueous of NH₄Cl andthen filtered through a plug of fluorisil eluting with additional DCM.The filtrate was dried with Na₂SO₄, filtered and concentrated to affordthe title compound (1.11 g, 92%) as a colorless oil. LC/MS [M−Me]=268.1.¹H NMR (500 MHz, CDCl₃) δ 7.14 (dd, J=13.4, 7.8 Hz, 1H), 7.02 (dd,J=13.4, 1.2 Hz, 1H), 4.01 (d, J=13.0 Hz, 1H), 3.87 (d, J=12.5 Hz, 1H),2.95 (d, J=13.2 Hz, 1H), 2.86 (d, J=12.5 Hz, 1H), 2.53 (d, J=7.8 Hz,1H), 2.23-2.28 (m, 1H), 2.17-2.22 (m, 1H), 1.75-1.82 (m, 2H), 1.55-1.72(m, 2H), 1.47 (s, 9H).

Step 6: tert-butyl(8-anti)-{1-[2-chloro-4-(trifluoromethyl)pyridin-3-yl]-2-nitroethyl}-3-azabicyclo[3.2.1]octane-3-carboxylate.A solution of LiCl-iPrMgCl (1.3 M in THF, 3.50 mL, 4.55 mmol) was slowlyadded to a solution of 2-chloro-3-iodo-4-(trifluoromethyl)pyridine (1.40g, 4.55 mmol) in THF (4.55 mL) at −40° C. The mixture was stirred 1 h at−40° C. and a pre-cooled solution of tert-butyl(8-anti)-8-[(E)-2-nitroethenyl]-3-azabicyclo[3.2.1]octane-3-carboxylate(1.10 g, 3.90 mmol) in THF (4.55 mL) was slowly added. The reaction wasstirred 10 min at −40° C., then the cold bath was removed and thereaction was stirred until it reached room temperature. The resultingmixture was quenched with a saturated solution of NH₄Cl. The aqueousphase was extracted with DCM and the combined organic phases were washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by silica gel column chromatography (heptane:EtOAc,100/0-55/45) to afford the title compound (1.26 g, 69%) as a yellowpowder. LC/MS [M+H-tBu]=408.2; ¹HNMR (400 MHz, CDCl₃) δ 8.57 (d, J=5.1Hz, 1H), 7.59 (d, J=5.1 Hz, 1H), 4.84-5.02 (m, 2H), 3.80-4.08 (m, 2H),3.67-3.77 (m, 2H), 2.71-3.01 (m, 4H), 2.09-2.24 (m, 1H), 1.83-1.95 (m,1H), 1.62-1.76 (m, 2H), 1.41-1.47 (m, 9H).

Step 7:1-[(8-anti)-{1-[2-chloro-4-(trifluoromethyl)pyridin-3-yl]-2-nitroethyl}-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one.To a solution of tert-butyl(8-anti)-{1-[2-chloro-4-(trifluoromethyl)pyridin-3-yl]-2-nitroethyl}-3-azabicyclo[3.2.1]octane-3-carboxylate(1.26 g, 2.72 mmol) in DCM (9 mL) was slowly added HCl (4M in dioxane,6.79 mL, 27.2 mmol) at room temperature. The mixture was stirred for 4hr at 50° C. The solvent was removed under reduced pressure. The residuewas suspended in DCM (9 mL) and was added to a saturated solution ofNaHCO₃ (25 mL). The mixture was stirred vigorously and isobutyrylchloride (314 μL, 3.00 mmol) was slowly added. The reaction wastransferred to a separating funnel and the phases were separated. Theaqueous layer was extracted twice with DCM and the combined organicphases were dried with Na₂SO₄, filtered and concentrated to provide thetitle compound (1.17 g, 98% yield) which required no furtherpurification. LC/MS [M+H]=434.0; ¹HNMR (400 MHz, CDCl₃) δ ppm 8.58 (d,J=5.1 Hz, 1H), 7.60 (d, J=5.1 Hz, 1H), 5.02-4.86 (m, 2H), 4.51-4.28 (m,2H), 3.84-3.68 (m, 2H), 3.28-3.14 (m, 1H), 2.89-2.66 (m, 3H), 2.35-2.18(m, 1H), 1.99-1.84 (m, 1H), 1.69-1.46 (m, 4H), 1.44-1.34 (m, 1H),1.20-1.05 (m, 6H).

Step 8:2-methyl-1-{(8-anti)[4-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}propan-1-one.Acetic acid (1.54 mL, 26.9 mmol) and zinc powder (1.23 g, 18.9 mmol)were successively added to a solution of1-[(8-anti)-{1-[2-chloro-4-(trifluoromethyl)pyridin-3-yl]-2-nitroethyl}-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one(1.17 g, 2.69 mmol) in THF (5.39 mL) were successively added at roomtemperature. The solution was stirred overnight at room temperature andthen refluxed at 90° C. for 6 h. The mixture was cooled to roomtemperature and then was filtered through a plug of Celite® eluting withDCM. The organic layer was concentrated. The crude product was purifiedby silica gel column chromatography (DCM:MeOH, 100:0-90:10) to affordthe title compound (342 mg, 35%) as a white powder. LC/MS [M+H]=368.1;¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=5.5 Hz, 1H), 6.58-6.64 (m, 1H),4.43 (dd, J=12.9, 2.7 Hz, 0.6H), 4.31 (dd, J=12.9, 3.3 Hz, 0.4H),3.80-3.62 (m, 1H), 3.56-3.40 (m, 2H), 3.32 (dd, J=9.4, 7.0 Hz, 1H),3.19-3.01 (m, 1H), 2.97-2.6 (m, 4H), 2.47-2.22 (m, 2H), 2.07-1.99 (m,1H), 1.97-1.68 (m, 3H), 1.61-1.43 (m, 2H), 1.19-1.00 (m, 6H).

Step 9:2-methyl-1-{(8-anti)-[1-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}propan-1-one.At room temperature, to a solution of2-methyl-1-{(8-anti)-[4-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}propan-1-one(342 mg, 0.93 mmol) in THF (3.1 mL) was added in one portion of NaH (60%in oil, 47 mg, 1.16 mmol) followed by methyl iodide (64 μL, 1.02 mmol).The mixture was stirred for 2 h and then was quenched with a saturatedsolution of NH₄Cl and diluted with DCM. The phases were separated andthe aqueous layer was extracted twice with DCM. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by silica gel column chromatography (heptane:EtOAc,100/0-0/100) to afford the title compound (197 mg, 56%) as a colorlessoil. LC/MS [M+H]=382.1; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=5.5 Hz,1H), 6.64 (t, J=5.9 Hz, 1H), 4.45 (dd, J=12.5, 3.1 Hz, 0.6H), 4.33 (dd,J=12.9, 3.9 Hz, 0.4H), 3.78 (dd, J=12.1, 3.5 Hz, 0.4H), 3.67 (dd,J=11.7, 2.7 Hz, 0.6H), 3.49 (t, J=9.8 Hz, 1H), 3.36 (t, J=8.6 Hz, 1H),3.16 (d, J=11.7 Hz, 0.6H), 3.12-3.04 (m, 1H), 3.01 (br. s., 3H),2.98-2.92 (m, 1H), 2.83-2.72 (m, 1.4H), 2.68 (d, J=13.3 Hz, 0.6H), 2.48(d, J=12.5 Hz, 0.4H), 2.29 (br. s., 0.6H), 2.25 (br. s., 0.4H),2.05-2.00 (m, 1H), 1.99-1.69 (m, 3H), 1.62-1.46 (m, 2H), 1.19-1.14 (m,3H), 1.10-1.03 (m, 3H).

Step 10:2-methyl-1-{(8-anti)-8-[1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}propan-1-one.Trifluoroacetic acid (118 μL, 1.55 mmol), followed by a premixedsolution of tetrabutylammonium nitrate (471 mg, 1.55 mmol) andtrifluoroacetic anhydride (215 μL, 1.55 mmol) in DCM (720 μL) were addedto a solution of2-methyl-1-{(8-anti)-[1-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}propan-1-one(197 mg, 0.516 mmol) in DCM (1.0 mL) at 0° C. The mixture was stirred 1h at 0° C. and 2 h at room temperature. The mixture was quenched with asaturated solution of NaHCO₃ until pH=8. The phases were separated andthe aqueous layer was extracted three times with DCM. The combinedorganic layers were dried with Na₂SO₄, filtered, and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography (heptane:EtOAc, 40:60-0:100) to afforded the titlecompound (138 mg, 63%) as a yellow powder. LC/MS [M+H]=425.1; ¹H NMR(400 MHz, CDCl₃) δ 8.69 (s, 1H), 7.34 (s, 1H), 4.53 (d, J=14.4 Hz, 1H),3.95 (s, 3H), 3.85 (d, J=12.5 Hz, 1H), 3.43 (d, J=12.5 Hz, 1H), 3.31 (s,1H), 2.92 (d, J=12.5 Hz, 1H), 2.86 (quin, J=6.6 Hz, 1H), 2.55-2.43 (m,2H), 1.90-1.58 (m, 4H), 1.24-1.08 (m, 6H).

Step 11:1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one.A saturated solution of NH₄Cl (0.442 mL) followed by zinc dust (55 mg,0.84 mmol) was added to a solution of2-methyl-1-{(8-anti)-[1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}propan-1-one(76 mg, 0.17 mmol) in a mixture of MeOH/THF (1:1, 2.7 mL) at roomtemperature. The mixture was stirred at room temperature for 10 min andwas filtered through a fritted plastic funnel eluting with DCM andwater. The phases were separated and the aqueous layer was extractedthree times with DCM. The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to provide thetitle compound which was immediately carried forward in the syntheticsequence and required no further purification. LC/MS [M+H]=395.1; ¹HNMR(400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.03 (s, 1H), 4.48 (dd, J=12.9, 2.7 Hz,1H), 3.86 (s, 3H), 3.83 (dd, J=12.1, 2.7 Hz, 1H), 3.41 (d, J=11.3 Hz,1H), 3.28 (br. s, 1H), 3.16 (s, 1H), 2.92 (d, J=12.5 Hz, 1H), 2.86(quin, J=7.0 Hz, 1H),1.14 (d, J=6.6 Hz, 3H), 2.44 (br. s., 1H), 2.38(br. s., 1H), 1.89-1.77 (m, 2H), 1.66-1.49 (m, 2H), 1.20 (d, J=7.0 Hz,3H). The structure of1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-onewas established by single crystal X-ray analysis (Example 107).

Step 12:3-cyano-N-(3-((1R,5S,8r)-3-isobutyryl-3-azabicyclo[3.2.1]octan-8-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.TEA (0.14 mL, 1.05 mmol) and 3-cyanobenzoyl chloride (75 mg, 0.46 mmol)were added sequentially at room temperature to a solution of1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one(138 mg, 0.35 mmol) in DCM (4.3 mL). The reaction was stirred overnightat room temperature and monitored by LCMS. Upon completion, the mixturewas poured into saturated sodium bicarbonate and extracted three timeswith DCM. The combined organic layers were dried with sodium sulfate andfiltered. The filtrate was concentrated and the residue was purifiedusing silica gel column chromatography (heptane/ethyl acetate,50/50-0/100) to give the title compound (31 mg, 22%) as a white powder:LC/MS [M−H]=522.5; ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 8.25 (s, 1H),8.17 (d, J=9.0 Hz, 1H), 7.94 (br. s., 1H), 7.89 (d, J=7.8 Hz, 1H), 7.69(t, J=7.4 Hz, 1H), 7.21 (s, 1H), 4.49 (d, J=13.7 Hz, 1H), 3.93 (s, 3H),3.88-3.80 (m, 1H), 3.42 (d, J=11.7 Hz, 1H), 3.31 (br. s., 1H), 2.93 (d,J=12.5 Hz, 1H), 2.86 (quin, J=6.6 Hz, 1H), 2.47 (br. s., 1H), 2.43 (br.s., 1H), 1.88-1.74 (m, 2H), 1.72-1.48 (m, 2H), 1.21-1.19 (m., 3H),1.15-1.13 (m, 3H).

Example 78-79

The following Examples 78-79 were prepared analogous to Example 77however employing the appropriate benzoic acid in Step 11 and theappropriate carboxylic acid in step 8.

Ex. Structure Name/Characterization 78

3-cyano-N-(3-((1R,5S,8r)-3-isobutyryl-3-azabicyclo[3.2.1]octan-8-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4- methoxybenzamide.LC/MS [M + H] = 554.3; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H), 8.13-8.19(m, 2H), 7.85 (s, 1H), 7.19 (s, 1H), 7.12 (m, 1H),4.49 (m, 1H), 4.05 (s,3H), 3.92 (s, 3H), 3.84 (m, 1H), 3.42 (m, 1 H), 3.31 (br. s, 1H), 2.93(m, 1H), 2.86 (m, 1H), 2.45- 2.50 (m, 1H), 2.38-2.45 (m, 1H), 1.70-1.89(m, 2H), 1.58 (m, 2H), 1.20 (m, 3H), 1.13 (m, 3H). 79

3-cyano-N-{3-((1R,5S,8r)-3-(cyclopentanecarbonyl)-3-azabicyclo[3.2.1]octan-8-yl]-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5- yl}benzamide. LC/MS [M +H] = 550.3; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H), 8.26 (s, 1H), 8.21-8.14 (m, 1H), 8.08-8.01 (m, 1H), 7.92-7.85 (m, 1H), 7.72-7.64 (m, 1H),7.20 (s, 1 H), 4.54-4.42 (m, 1H), 3.92 (s, 3H), 3.90-3.83 (m, 1H),3.44-3.35 (m, 1H), 3.31 (br. s., 1H), 3.00-2.86 (m, 2H), 2.50-2.37 (m,2H), 1.94-1.50 (m, 12H).

Example 80 Preparation of3-cyano-N-(3-((3R,4R)-1-isobutyryl-3-methylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1: tert-butyl3-methyl-4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate.A solution of1-methyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(prepared as described in Example 65, 1 g, 2.7 mmol), tert-butyl3-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(Janssen, R. D. et al. WO2014/23815) (743 mg, 2.2 mmol) and K₂CO₃ (1.12g, 8.1 mmol) in 1,4-dioxane (20 mL) was degassed using Argon for 1 h. Tothe above reaction mixture was introduced Pd(PPh₃)₄ (156 mg, 0.14 mmol)and the mixture was heated at 80° C. for 1 h under microwaveirradiation. The reaction mixture was filtered through a pad of Celite®and the filtrate was extracted using EtOAc. The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by silica gel columnchromatography (EtOAc:hexane, 10:90-15:85) to afford the title compound(620 mg, 52%). ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 7.32 (s, 1H),5.45-5.62 (m, 1H), 4.36-4.12 (m, 1H), 3.96 (s, 3H), 3.87-3.72 (m, 2H),3.42-3.38 (m, 1H), 2.60-2.45 (m, 1H), 1.50 (s, 9H), 0.95 (d, J=7.0 Hz,3H).

Step 2: tert-butyl4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpiperidine-1-carboxylate.A solution of tert-butyl3-methyl-4-(1-methyl-5-nitro-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate(600 mg, 0.14 mmol), Pd(OH)₂/C (1.2 mg, 20% w/w) and ammonium formate(8.59 g, 136 mmol) in 50 mL of EtOH/H₂O (1:1) was heated at 80° C. for48 h. The reaction mixture was cooled to room temperature, filteredthrough a pad of Celite® and washed with MeOH and DCM. The filtrate wasconcentrated to dryness and the crude residue obtained was diluted withwater and extracted with DCM. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated toafford the title compound (450 mg, 80%), which was used without furtherpurification in the subsequent step. LC/MS [M+H]=413.4

Step 3: tert-butyl4-(5-(3-cyanobenzamido)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpiperidine-1-carboxylate.To a stirred solution of tert-butyl4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpiperidine-1-carboxylate(450 mg, 0.11 mmol) and TEA (0.45 mL, 0.33 mmol) in DCM (25 mL) at 0° C.was added 3-cyanobenzoyl chloride (218 mg, 0.13 mmol), followed bycatalytic DMAP. The cooling bath was removed, and the reaction mixturewas stirred at room temperature for 16 h. The reaction mixture wasquenched with 10% NaHCO₃ solution and extracted with DCM. The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by silica gel columnchromatography (MeOH:DCM, 2:98-4:96) to provide the title compound (190mg, 32%). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J=7.0 Hz, 1H), 8.23 (s,1H), 8.16 (d, J=7.7 Hz, 1H), 7.97 (d, J=16.7 Hz, 1H), 7.88 (d, J=7.7 Hz,1H), 7.67 (t, J=7.7 Hz, 1H), 7.15 (s, 1H), 4.37-4.20 (m, 1H), 3.92 (s,3H), 3.34 (d, J=12.8 Hz, 1H), 3.04-2.86 (m, 2H), 2.79-2.70 (m, 1H), 2.55(d, J=12.4 Hz, 1H), 2.01 (d, J=7.7 Hz, 1H), 1.91 (d, J=12.8 Hz, 1H),1.48 (d, J=7.4 Hz, 9H), 0.71 (d, J=7.0 Hz, 3H); LC/MS [M+H]=542.3.

Step 4:3-cyano-N-(1-methyl-3-(3-methylpiperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.To a stirred solution of tert-butyl4-(5-(3-cyanobenzamido)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpiperidine-1-carboxylate(190 mg, 0.35 mmol) in MeOH (10 mL) at 0° C. was added 4M HCl in dioxane(2 mL) and the reaction mixture was warmed to room temperature andstirred for 4 h. The reaction mixture was concentrated and the residueobtained was dissolved in MeOH and basified using carbonate resin. Theresulting solution was filtered and washed with MeOH. The filtrate wasconcentrated to afford the title compound (150 mg, 96%). LC/MS[M+H]=442; ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.44-8.39 (m, 1H),8.32-8.27 (m, 2H), 8.13-8.09 (m, 1H), 7.83-7.76 (m, 1H), 7.68-7.64 (m,1H), 3.89 (s, 3H), 3.54-3.42 (m, 2H), 3.16-3.12 (m, 1H), 3.07-3.02 (m,1H), 2.81-2.77 (m, 1H), 1.96 (s, 1H), 1.86-1.77 (m, 2H), 1.46-1.41 (m,1H), 0.79 (s, 3H).

Step 5:3-cyano-N-(3-(1-isobutyryl-3-methylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.To a solution of3-cyano-N-(1-methyl-3-(3-methylpiperidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide(150 mg, 0.34 mmol) and TEA (131 μL, 1.02 mmol) in DCM (10 mL) at 0° C.was added isobutyryl chloride (43 μL, 0.41 mmol). The cooling bath wasremoved, and the reaction mixture was stirred at room temperature for 1h. The reaction mixture was basified using 10% NaHCO₃ and extracted withDCM. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The crude product was purified bypreparative HPLC to provide the title compound (69 mg, 40%) as anoff-white solid. LC/MS [M+H]=512.1; ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d,J=6.9 Hz, 1H), 8.24 (s, 1H), 8.17 (d, J=7.7 Hz, 1H), 8.05-7.92 (m, 1H),7.88 (d, J=7.7 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 7.17 (s, 1H), 3.93 (s,3H), 3.51-3.34 (m, 1H), 3.24-3.09 (m, 1H), 2.92-2.81 (m, 2H), 2.72-2.56(m, 1H), 2.30 (t, J=11.8 Hz, 1H), 2.16-2.01 (m, 1H), 1.23-1.11 (m, 8H),0.80 (d, J=6.0 Hz, 3H).

Step 6:3-cyano-N-(3-((3R,4R)-1-isobutyryl-3-methylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.Racemic3-cyano-N-(3-(1-isobutyryl-3-methylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide(125 mg) was resolved by chiral supercritical fluid chromatography (LuxCellulose-4, 250 mm×21.2 mm, 5 μm, MeOH/CO₂, 40%, 80 mL/min). Isolationof the first eluting cis-isomer (rt=8.793) afforded the title compound(34 mg). LC/MS [M+H]=512.2; ¹H NMR (400 MHz, CDCl₃) δ 8.85 (br s, 1H),8.51-8.17 (m, 3H), 7.84 (s, 1H), 7.65-7.60 (m, 1H), 7.12-7.09 (m, 1H),4.85-4.53 (m, 1H), 3.91-3.84 (m, 5H), 3.43-3.34 (m, 2H), 2.89-2.65 (m,2H), 2.11-1.97 (m, 2H), 1.72-1.69 (m, 2H), 1.25-1.07 (m, 6H), 0.72-0.70(M, 2H), 0.40-0.38 (m, 1H). Absolute stereochemistry has been assignedbased on potency comparison of enantiomers and the correspondingconfiguration of Example 84 determined through a co-crystal X-raystructure.

Example 81-82

Examples 81 and 81 was prepared analogous to Example 80 employing theappropriate acid chloride in step 4 and 6. Absolute stereochemistry hasbeen assigned based on potency comparison of enantiomers and thecorresponding configuration of Example 84 determined through aco-crystal X-ray structure.

Ex. Structure Name/Characterization 81

3-cyano-N-(3-((3R,4R)-1-(cyclopentane-carbonyl)-3-methylpiperidin-4-yl)-1-methyl-4-(trifluoro-methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 538.5; Chiral LC:Rt = 1.60 min (Method E); ¹H NMR (400 MHz, CD₃OD) δ 8.40-8.20 (m, 3H),8.01-7.95 (m, 1H), 7.80-7.70 (m, 1H), 7.55-7.50 (m, 1H) 4.80-4.70 (m,1H), 4.58-4.50 (m, 1H), 4.30-4.20 (m, 1H), 4.10-4.05 (m, 1H), 3.93 (s,3H), 3.58-3.45 (m, 2H), 3.30-3.05 (m, 2H), 2.95-2.85 (m, 1H), 2.80-2.70(m, 1H), 2.20-2.05 (m, 2H), 2.05-1.55 (m, 5H), 0.80-0.65 (m, 3H). 82

3-cyano-2-fluoro-N-(3-((3R,4R)-1-isobutyryl-3-methylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 530.5; ¹H NMR (400MHz, CD₃OD) δ 8.35 (s, 1H), 8.11 (t, J = 7.0 Hz, 1H), 7.98 (t, J = 6.8Hz, 1H), 7.47- 7.58 (m, 2H), 4.76 (d, J = 14.4 Hz, 1H), 4.57 (d, J =12.1 Hz, 1H), 4.24 (d, J = 11.3 Hz, 1H), 4.04 (d, J = 14.4 Hz, 1H), 3.93(s, 3H), 3.37-3.59 (m, 2H), 3.20- 3.28 (m, 1H), 2.95-3.17 (m, 2 H), 2.91(d, J = 13.3 Hz, 1 H), 2.76 (t, J = 13.1 Hz, 1H), 1.99-2.26 (m, 3H),1.62- 1.84 (m, 2H), 1.20 (d, J = 6.6 Hz, 2H), 1.02-1.15 (m, 5H),0.65-0.80 (m, 4H).

Example 83 Preparation of3-cyano-N-(3-((3R,4R)-1-(2-cyclopropylacetyl)-3-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1. tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate. To a Parrvessel charged with 1-benzyl-3-methylpiperidone (25.0 g, 120 mmol) inethyl acetate (122 mL) was added di-tert-butyl dicarbonate (27.4 g, 122mmol), and Pd(OH)₂/C (20%) (8.55 g). The vessel was sealed and itsatmosphere replaced with hydrogen four times. On the fifth recharge, thehydrogen gas pressure was set to 100 psi. The vessel was shook for 4 hat room temperature and then the atmosphere was brought to ambientconditions. The mixture was filtered through a pad of Celite® and thefilter cake was washed with ethyl acetate. The filtrates were thenconcentrated and residue was purified by silica gel columnchromatography (DCM:EtOAc, 100:0-70:30) to afford the title compound(20.6 g, 79%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.14-4.23(m, 2H), 3.20-3.32 (m, 1H), 2.86 (br. s., 1H), 2.34-2.60 (m, 3H), 1.50(s, 9H), 1.05 (d, J=6.6 Hz, 3H).

Step 2. tert-butyl3-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.To a solution of LDA (28 mL of 2.0 M in THF, 56.0 mmol) in THF (68 mL)at −78° C. was added tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate(11.9 g, 56.0 mmol), and N-phenyl triflimide (22.0 g, 56.0 mmol),sequentially. The mixture was allowed to warm to room temperature andwas then quenched with saturated aqueous ammonium chloride (50 mL). Thephases were separated. The organic layer was filtered and concentrated.The crude residue was purified by silica gel column chromatography(Heptane:EtOAc, 75:25-0:100) to give the title compound (14.9 g, 77%) asa colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.65-5.82 (m, 1H), 3.88-4.26(m, 2H), 3.52-3.76 (m, 1H), 3.30-3.51 (m, 1H), 2.55-2.71 (m, 1H), 1.48(s, 9H), 1.16 (d, J=7.0 Hz, 3H).

Step 3. tert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate.To a RB flask equipped with a condenser was sequentially addedtert-butyl3-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(14.2 g, 40.8 mmol),1,4-dimethyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(prepared as described in Example 58) (14.1 g, 40.8 mmol), potassiumphosphate tribasic (19.1 g, 89.9 mmol), and palladium(tetrakis)triphenylphosphine (4.7 g, 4.08 mmol). The mixture wassuspended in water:dioxane (1:1, 430 mL), and was heated to 90° C. for18 hours. After cooling, the mixture was filtered through a pad ofsilica gel. The filtrate was absorbed onto silica and purified twice bysilica gel column chromatography (DCM:EtOAc, 50:50-0:100) to give thetitle compound (13.2 g, 84%) as an off-white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.98 (s, 1H), 7.06 (s, 1H), 5.61-5.76 (m, 1H), 4.05-4.43 (m,2H), 3.90 (s, 3H), 3.69-3.85 (m, 1H), 3.36-3.54 (m, 1H), 2.81 (s, 3H),2.44-2.62 (m, 1H), 1.52 (s, 9H), 0.98 (d, J=6.63 Hz, 3H).

Step 4. (R,R)-tert-butyl4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpiperidine-1-carboxylate.To a pressure vessel charged with tert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate(13.24 g, 34.26 mmol) in MeOH (69 mL) was added triethylamine (7.14 mL,51.4 mmol) and palladium hydroxide (4.81 g, 3.43 mmol). The vessel wassealed and its atmosphere was replaced with hydrogen gas at 100 psi. Thevessel was then agitated for 24 h at room temperature. The mixturefiltered through a pad of celite. The filtrate was concentrated toafford the crude product as a mixture of cis:trans isomers (ca 13:1).The mixture was purified by chromatography through a pad of silica gel(DCM:EtOAc, 100:0-0:100) to remove the minor diastereomer. The majorisomer was resolved by chiral chromatography (Chiral Tech OJ-H, 21.2×500mm, 5 μm, 0-10% MeOH in CO₂, 80.0 mL/min) to afford two peaks which weredistinguishable by the following method: ChiralTech OJ-H 250, 4.6×250mm, 5 μm, 0-10% MeOH (0.2% NH₄+) in CO₂, 3 mL/min, 10 min. The firstpeak eluted at 4.46 min, and the second peak eluted at 5.13 min. Thesecond peak corresponded to the (R,R) stereochemistry as established byX-ray co-crystal analysis of Example 84. The second peak was collectedto give the title compound (5.9 g, 48%) as a white solid ¹H NMR (400MHz, CDCl₃) δ 7.89 (s, 1H), 6.78 (s, 1H), 4.19-4.46 (m, 1.5H), 3.98-4.18(m, 1.5H), 3.80 (s, 3H), 3.39 (dt, J=12.5, 3.1 Hz, 1H), 2.97-3.16 (m,1.5H), 2.74-2.94 (m, 1.5H), 2.49 (s, 3H), 2.07-2.18 (m, 1H), 1.93-2.07(m, 1H), 1.66 (d, J=14.0 Hz, 1H), 1.49 (s, 9H), 0.70 (d, J=7.0 Hz, 3H).

Step 5. tert-butyl(3R,4R)-4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpiperidine-1-carboxylate.To a round-bottomed flask charged with (R,R)-tert-butyl4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpiperidine-1-carboxylate(5.71 g, 15.9 mmol), DCM (106 mL), and triethylamine (4.44 mL, 31.9mmol) was added 3-cyanobenzoyl chloride (2.9 g, 17.5 mmol) and acatalytic amount of DMAP. The mixture was stirred at room temperaturefor 15 h and then was poured into saturated sodium bicarbonate (100 mL).The organic layer was concentrated and the residue was purified bysilica gel column chromatography (DCM:EtOAc, 70:30-100:0) to give thetitle compound (7.2 g, 93%) as an off-white solid. LCMS [M+H]=488.2.

Step 6.3-cyano-N-(3-((3R,4R)-1-(2-cyclopropylacetyl)-3-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.Trifluoroacetic acid (5 mL) was added to a suspension of tert-butyl(3R,4R)-4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpiperidine-1-carboxylate(80 mg, 0.17 mmol) in DCM (10 mL). The mixture was stirred for 2 h atroom temperature and then concentrated. The residue was suspended in TEA(52.7 mg, 0.521 mmol), DCM (10 mL), and 2-cyclopropylacetyl chloride(30.9 mg, 0.261 mmol) at 20° C. The resulting solution was stirred for 4h and then was poured into aqueous sodium bicarbonate. The organic layerwas concentrated and the crude product was purified by silica gel columnchromatography to give the title compound (30 mg, 43%) as an off-whitesolid. LC/MS [M+H]=470.1; Chiral SFC: Rt=1.738 min (Method M); ¹H NMR(400 MHz, CDCl₃) δ 8.32-8.31 (m, 3H), 8.04 (s, 0.5H), 7.78 (s, 1H), 7.80(s, 0.5H), 7.68-7.66 (m, 1H), 6.89 (s, 1H), 4.91-4.87 (m, 0.5H),4.64-4.60 (m, 0.5H), 4.03-4.00 (m, 0.5H), 3.85-3.77 (m, 4H), 3.51-3.48(m, 1H), 3.39-3.36 (m, 0.5), 3.23-3.19 (m, 0.5H), 2.78-2.74 (m, 0.5H),2.70-2.62 (m, 3.5H), 2.41-1.99 (m, 3.5H), 1.76-1.73 (m, 1H), 1.13-1.08(m, 1H), 0.62-0.61 (m, 1.5H), 0.59-0.57 (m, 3.5H), 0.23-0.17 (m, 2H).

Examples 84-87 & 112

The following Examples 84-87 and 112 were prepared analogous to Example83 employing the appropriate carboxylic acid or carboxylic acid chloridecoupling partners in Steps 5 and 6. Absolute stereochemistry has beenassigned based on potency comparison of enantiomers and thecorresponding configuration of Example 84 determined through aco-crystal X-ray structure.

Ex. Structure Name/Characterization 84

3-cyano-N-(3-((3R,4R)-1-(cyclopentanecarbonyl)-3-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 484.2; ¹H NMR (400 MHz, CD₃OD)δ 8.37 (s, 1 H), 8.34- 8.26 (m, 1 H), 8.12 (s, 1 H), 7.96 (d, J = 7.8Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.16 (d, J = 6.2 Hz, 1 H), 4.74 (d,J = 13.3 Hz, 1H), 4.26 (d, J = 14.1 Hz, 1H), 4.07 (s, 3H), 3.82 (s, 3H), 3.62 (dd, J = 7.8, 4.3 Hz, 1 H), 3.48 (dd, J = 13.5, 2.2 Hz, 1 H),3.28-3.04 (m, 2 H), 2.72-2.64 (s, 3 H), 2.31-2.16 (m, 1 H), 2.09- 1.93(m, 1 H), 1.88-1.60 (m, 9 H), 0.73 (d, J = 7.0 Hz, 1.5 H), 0.66 (d, J =6.6 Hz, 2 H). 85

3-cyano-N-(3-((3R,4R)-1-isobutyryl-3-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide. LC/MS [M +H] = 458.2; ¹H NMR (400 MHz, CD₃OD) δ 8.46-8.29 (m, 2 H), 8.13 (s, 1 H),7.98 (d, J = 7.8 Hz, 1 H), 7.75 (t, J = 7.6 Hz, 1 H), 7.17 (d, J = 5.1Hz, 1 H), 4.58 (d, J = 12.9 Hz, 1 H), 4.24 (d, J = 10.9 Hz, 1 H), 3.83(s, 3 H), 3.64 (d, J = 8.6 Hz, 1 H), 3.50 (d, J = 17.2 Hz, 1 H),3.16-2.89 (m, 2 H), 2.35-1.99 (m, 3 H), 1.88-1.62 (m, 1 H), 1.15- 1.04(m, 6 H). 112

3-cyano-N-(3-((3R,4R)-1-isobutyryl-3-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4- methoxybenzamide.LC/MS [M + H] = 488.2; ¹H NMR (400 MHz, CDC1₃) δ 8.64 (br s, 0.5 H),8.31-8.19 (m, 3 H), 8.06 (br s, 0.5 H), 7.07 (t, J = 6.4 Hz, 1 H), 6.83(d, J = 14.0 Hz, 1 H), 4.85 (d, J = 13.2 Hz, 0.5 H), 4.56 (d, J = 13.2Hz, 0.5 H), 4.13 (d, J = 13.2 Hz, 0.5 H), 4.02 (s, 3 H), 3.89 (d, J =13.2 Hz, 0.5 H), 3.82 (d, J = 13.6 Hz, 3 H), 3.48-3.46 (m, 1 H),3.42-3.38 (m, 0.5 H), 3.21- 3.17 (m, 0.5 H), 2.91-2.82 (m, 1.5 H),2.75-2.66 (m, 0.5 H), 2.56 (s, 3 H), 2.40 (br s, 0.5 H), 2.05-1.97 (m,1.5 H), 1.77-1.72 (m, 1 H), 1.26-1.12 (m, 6 H), 0.72 (d, J = 6.8 Hz, 1.5H), 0.36 (d, J = 6.8 Hz, 1.5 H). 86

3-cyano-N-(3-((3R,4R)-1-(2-cyclopropylpropanoyl)-3-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 484.2. Chiral SFC: Rt = 1.844min (Method M). ¹HNMR (400 MHz, CDCl₃) δ 8.38-8.21 (m, 3.5H), 7.86 (s,br, 1.5H), 7.68-7.65 (m, 1H), 6.88-6.85 (m, 1H), 4.93- 4.89 (m, 0.5H),4.66-4.63 (m, 0.5H), 4.05-4.02 (m, 0.5H), 3.85-3.76 (m, 3.5H), 3.51-3.48(m, 1H), 3.41- 3.37 (m, 0.5H), 3.18-3.16 (m, 0.5H), 2.89-2.61 (m, 4H),2.18-1.29 (m, 4H), 1.62-1.14 (m, 4H), 0.71-0.68 (m, 1.5H), 0.55-0.48 (m,3.5H), 0.18-0.09 (m, 2H). 87

3-cyano-N-(3-((3R,4R)-1-(cyclopentanecarbonyl)-3-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-methoxyethoxy)benzamide. LC/MS [M + H] = 558.3; ¹HNMR (400 MHz, DMSO-d₆) δ ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H),8.34-8.26 (m, 3H), 8.02 (s, 1H), 7.06 (d, J = 6.2 Hz, 1H), 6.80-6.81 (m,1H), 4.84 (d, J = 13.3 Hz, 1H), 4.56 (d, J = 14.1 Hz, 1H), 4.37 (s, 3H),4.15-4.10 (m, 1H), 3.97-3.65 (m, 5 H), 3.50-3.35 (m, 3 H), 3.28-3.04 (m,2 H), 2.72-2.64 (s, 3 H), 2.20-2.05 (m, 2 H), 2.04-1.50 (m, 13 H), 0.73(d, J = 7.0 Hz, 2 H), 0.66 (d, J = 6.6 Hz, 2 H).

Examples 88-89

The following Examples 88-89 were prepared analogous to Example 83employing rac-3,3,3-trifluoro-2-methylpropanoic acid in Step 6. Theproduct was resolved by chiral SFC (Lux cellulose-1, 250×21.2 mm, 5 μm,CO₂/MeOH-0.2% NH₃, 70/30, 80 mL/min). The absolute configuration wasdetermined by independent synthesis from the enantiopure2-trifluoromethylpropionic acid obtained by the method described byO'Hagan, et al, Tetrahedron: Asym., 2004, 15(16), 2447-2449.

Ex. Structure Name/Characterization 88

3-cyano-N-(1,4-dimethyl-3-((3R,4R)-3-methyl-1-((R)-3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 512.2; Chiral SFC:Rt = 6.747 min (Method D); ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (s, 1H),8.44 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.97-8.12 (m, 2H), 7.76 (t, J =8.0 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1 H), 4.33-4.62 (m, 1H), 4.00-4.24 (m,1H), 3.93 (d, J = 9.8 Hz, 1H), 3.69- 3.77 (m, 3H), 3.54 (t, J = 12.1 Hz,1H), 3.43 (d, J = 12.5 Hz, 1H), 3.12-3.26 (m, 1H), 2.95 (d, J = 12.1 Hz,1H), 2.75 (t, J = 12.1 Hz, 1H), 1.82-2.19 (m, 5H), 1.67 (br. s., 3H),1.09-1.35 (m, 11H), 0.45-0.71 (m, 7H). 89

3-cyano-N-(1,4-dimethyl-3-((3R,4R)-3-methyl-1-((S)-3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 512.2; Chiral SFC:Rt = 7.084 min min (Method D); ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (s,1H), 8.46 (s, 1H), 8.35-8.26 (m, 1H), 8.12-8.02 (m, 2H), 7.83-7.73 (m,1H), 7.27 (s, 1H), 4.63-4.53 (m, 0.5H), 4.48-4.39 (m, 0.5H), 4.25-4.00(m, 2H), 3.77 (s, 3H), 3.61-3.52 (m, 1H), 3.51-3.44 (m, 0.5H), 3.29-3.20(m, 0.5H), 2.99-2.91 (m, 0.5H), 2.86-2.76 (m, 0.5H), 2.52 (s, 3H),2.18-1.87 (m, 2H), 1.73-1.61 (m, 1H), 1.29-1.21 (m, 3H), 0.66-0.60 (m,1.5H), 0.59-0.52 (m, 1.5H).

Example 90 Preparation of3-cyano-N-(3-((2S,4R)-1-(cyclopentanecarbonyl)-2-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide

Step 1: (S)-1-(cyclopentanecarbonyl)-2-methylpiperidin-4-one. A flaskwith a mixture of benzyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (500mg, 2.02 mmol) and Pd/C (5% by weight, 215 mg) in EtOH (10 mL) wasevacuated and then put under hydrogen gas. The mixture was stirred under1.1 bar hydrogen over pressure for 1 h. The mixture was filtered througha Celite® plug, and the filtrate was concentrated in vacuo. To theresidue was added DCM (10 ml) followed by TEA (1.41 mL, 10.1 mmol) andthen cyclopentanecarbonyl chloride (492 μL, 4.04 mmol) was addeddropwise. The reaction mixture was stirred at room temperature for 1 h,whereupon the reaction was quenched with 40 mL water followed byextraction with DCM (4×). The combined organic extracts were evaporatedand the residue was purified by silica gel column chromatography(EtOAc/heptane; 1:1) to provide the title compound (301 mg, 71%) as acolorless oil. ¹H NMR (500 MHz, CDCl₃) δ 5.24-4.84 (2 br s, 1H),4.64-4.10 (2 br s, 1H), 3.55-3.11 (2 br s, 1H), 2.95 (m, 1H), 2.65 (dd,J=6.7, 14.4 Hz, 1H), 2.50-2.30 (m, 3H), 1.93-1.77 (m, 6H), 1.64-1.56 (m,2H), 1.29-1.16 (m, 3H).

Step 2:(S)-1-(cyclopentanecarbonyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate. n-BuLi (2.5M solution in hexanes, 1.15 mL,2.87 mmol) was added dropwise to diisopropylamine (402 μL, 2.87 mmol) indry THF (5 mL) under nitrogen at −78° C. The mixture was stirred at −78°C. for 30 min, whereupon(S)-1-(cyclopentanecarbonyl)-2-methylpiperidin-4-one (300 mg, 1.43 mmol)in dry THF (4 mL) was added. After 30 min,N-phenyl-bis(trifluoromethanesulfonimide) (1.02 g, 2.86 mmol) was added.The temperature was allowed to warm to room temperature. After stirringfor 30 min, the reaction mixture was cooled to 0° C. and the reactionwas quenched with NaHCO₃ (50% sat.) and extracted with diethyl ether.The organic phase was washed with citric acid (10%), NaOH (1 M), waterand brine. The organic phase was dried (Na₂SO₄) and evaporated. Theresidue was purified by silica gel column chromatography (EtOAc/heptane,15:85-2:8) to provide the title compound (329 mg, 67%) as an orange oil.¹H NMR (500 MHz, CDCl₃) δ 5.81-5.74 (m, 1H), 5.29-3.26 (m, 3H),2.90-2.52 (m, 2H), 1.98-1.53 (m, 8H), 1.35-1.15 (m, 3H).

Step 3:(S)-cyclopentyl(4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyl-3,6-dihydropyridin-1(2H)-yl)methanone.(S)-1-(cyclopentanecarbonyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate (182 mg, 0.95 mmol),1,4-dimethyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(prepared as described in Example 58, 300 mg, 0.95 mmol), tetrakistriphenylphosphine Pd(0) (109 mg, 0.09 mmol) and K₃PO₄ (442 mg, 2.08mmol) were stirred in dioxane/water 9:1 at 60° C. under an atmosphere ofnitrogen overnight. The mixture was concentrated to dryness, whereuponwater and DCM were added. The phases were separated and the organiclayer was evaporated. The residue was purified by silica gel columnchromatography (EtOAc/heptane; 3:7-6:4) to provide the title compound(221 mg, 61%) as a yellow solid foam. LC/MS [M+H]=383.

Step 4:3-cyano-N-(3-((2S,4S)-1-(cyclopentanecarbonyl)-2-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methoxybenzamide.A mixture of(S)-cyclopentyl(4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyl-3,6-dihydropyridin-1(2H)-yl)methanone(59 mg, 0.15 mmol), Pd/C (5% by weight, 24 mg), TEA (24 μL, 0.17 mmol)in EtOH (96%, 5 mL) was stirred under 5 bar of hydrogen for 6 h. Themixture was filtered through Celite® and the filtrate was concentrated.The residue was dissolved in DMF (1 mL) and a solution of3-cyano-5-methoxybenzoic acid (30 mg, 0.17 mmol), HATU (54 mg, 0.17mmol) and DIEA (56 μL, 0.34 mmol) in DMF (1 mL) was added. The mixturewas stirred at room temperature overnight. The reaction mixture waspurified by preparatory HPLC to provide the title compound (22 mg, 27%)as a white powder. LCMS [M+H]=514; ¹H NMR (500 MHz, CDCl₃) δ 8.31 (s,1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.30 (s, 1H), 6.95 (s, 1H), 4.27 (br s,1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.90 (m, 1H), 3.21 (br s, 1H), 3.07 (m,1H), 2.87 (m, 1H), 2.58 (s, 3H), 2.26 (br s, 1H), 2.02 (br s, 1H),1.88-1.66 (m, 6H), 1.61-1.52 (m, 4H), 1.17 (d, J=6.0 Hz, 3H).

Example 91 Preparation of3-cyano-N-(1,4-dimethyl-3-((2S,4R)-2-methyl-1-((S)-3,3,3-trifluoro-2-methylpropanoyl)-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1. tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate. Asuspension of benzyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (600 mg,2.43 mmol), palladium on carbon (100 mg, wet), ethanol (5 mL) and THF (5mL) was treated with Boc₂O (582 mg, 2.67 mmol) and subjected to Parrhydrogenation at 15 psi for 18 hours at room temperature. The reactionwas filtered through Celite® and washed with ethanol (3×15 mL). Thecombined filtrates were concentrated in vacuum. The crude product waspurified by silica gel column chromatography (PE:EtOAc, 100:0-90:10) toafford the title compound (500 mg, 96.6%) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 4.70 (s, 1H), 4.24-4.19 (m, 1H), 3.32-3.27 (m, 1H),2.68-2.45 (m, 4H), 1.47 (s, 9H), 1.17-1.15 (m, 3H).

Step 2. tert-butyl(S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.To a solution of (S)-2-methyl-4-oxopiperidine-1-carboxylate (213 mg,0.99 mmol) in THF (20 ml) was slowly added a solution of NaHMDS (2 mL, 2mmol) at −78° C. under nitrogen (in oven-dried glassware). After 30minutes, a solution of N-phenyl bis(trifluoromethanesulfonimide (714 mg,2.0 mmol) in THF (8 ml) was slowly added. The reaction mixture was leftstirring overnight, by which time it was slowly warmed to roomtemperature. The solvent was removed at 35° C. and the resulting residuewas purified by column chromatography on neutral Al₂O₃ (PE:EtOAc, 30:1)to afford the title compound (317 mg, 91.9%) as colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 5.74-5.70 (m, 1H), 4.66 (br s, 1H), 4.44-4.39 (m,1H), 3.65-3.61 (m, 1H), 2.98-2.75 (m, 1H), 2.57-2.04 (m, 1H), 1.67-1.16(m, 11H).

Step 3. tert-butyl(S)-4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate.A solution of tert-butyl(S)-2-methyl-4-(((trifluoromethyl)-sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(424 mg, 1.23 mmol),1,4-dimethyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(prepared as in Example 58) (389 mg, 1.23 mmol), and K₃PO₄ (521 mg, 2.46mmol) in a mixed solvent of dioxane/H2O (9 mL, 8/1) was degassed usingN₂ for 10 min. Pd(PPh3)4 (142 mg, 0.123 mmol) wad added, again degassedfor 10 min and then heated at 100° C. for 4 h. The mixture wasconcentrated and the resulting residue was partitioned between H₂O (20mL) and DCM (20 mL). The organic layer was dried, concentrated, andpurified by silica gel column chromatography (DCM followed by PE:EtOAc,85:15-80:20) to afford the title compound as a yellow solid. LCMS[M+H]=387.1.

Step 4. tert-butyl(2S,4R)-4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpiperidine-1-carboxylate.A solution of tert-butyl(S)-4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate(76 mg, 0.2 mmol) and ammonium formate (13.5 mg, 0.214 mmol) in EtOH (10mL) was heated to reflux in presence of Pd/C (76 mg, 20% by wt) for 14h. The reaction mixture was filtered through a pad of Celite® and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (PE:EtOAc, 50:50-100:0). The racemic product was resolvedby chiral SFC (ChiralCel OJ, 300×50 mm, 10 μm, CO₂/EtOH—NH₃H₂O, 80:20,180 mL/min). Two peaks were recovered, and analyzed using the followingmethod: Ultimate XB-C18, 3 μm, 3.0×50 mm, 1-100% MeCN in water (0.1%TFA), 15 min. The first peak eluted at 5.61 min. The second eluting peakeluted at 6.34 min. The second eluting peak was collected andconcentrated to afford the title compound. LCMS [M+H]=359.1.

Step 5. tert-butyl(2S,4R)-4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpiperidine-1-carboxylate.tert-Butyl(2S,4R)-4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpiperidine-1-carboxylate(500 mg, 1.39 mmol) was dissolved in DCM (20 mL), and TEA (212 mg, 2.09mmol) was added. The solution was cooled to 0° C. Then 3-cyanobenzoylchloride (254 mg, 1.53 mmol) in DCM (10 mL) was added over a period of10 min. After addition, the solution was stirred at 0° C. for 1 h. Thereaction was quenched by water (20 mL), and extracted with DCM (20mL×2). The combined oranic layers were dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified via silica gel columnchromatography (PE/EtOAc, 70:30-47:63) to give the title compound asyellow solid. LCMS [M+H]=359.1.

Step 6.3-cyano-N-(1,4-dimethyl-3-((2S,4R)-2-methylpiperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamidehydrochloride. tert-Butyl(2S,4R)-4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpiperidine-1-carboxylate(590 mg, 1.2 mmol) was dissolved in dixoane (15 mL), and 4M HCl/Dioxane(15 mL) was added drop wise at an ice-water bath. The mixture wasstirred at 20° C. for 16 h. The mixture was concentrated to afford thetitle compound (600 mg). LCMS [M+H]=488.1.

Step 7.3-cyano-N-(1,4-dimethyl-3-((2S,4R)-2-methyl-1-((S)-3,3,3-trifluoro-2-methylpropanoyl)-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.3-Cyano-N-(1,4-dimethyl-3-((2S,4R)-2-methylpiperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamidehydrochloride (600 mg, 1.3 mmol) was dissolved in DMF (20 mL) and DIPEA(505 mg, 3.91 mmol) was added, followed byrac-3,3,3-trifluoro-2-methylpropanoic acid (185 mg, 1.3 mmol) and HATU(743 mg, 1.95 mmol). The reaction solution was stirred at 25° C. for 1h. The reaction was quenched by brine (20 mL), and extracted with EtOAc(20 mL×3). The combined organic layers were dried over Na₂SO₄, filtered,and concentrate. The crude product was purified by silica gel columnchromatography (EtOAc:PE, 50:50-80:20). The mixture of diastereomers wasseparated by chiral SFC (ChiralCel OJ, 250×30 mm, 5 μm, CO₂/EtOH—NH₃H₂O,80/20, 60 mL/min) and the first eluting isomer was isolated to affordthe title compound (170 mg). LC/MS [M+H]=512.1. Chiral SFC: Rt=4.202 min(Method N). ¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.34-8.31 (m, 1H),8.15 (s, 1H), 8.01-7.98 (m, 1H), 7.79-7.75 (m, 1H), 7.25 (s, 1H),5.06-5.03 (m, 0.5H), 4.85-4.83 (m, 1H), 4.66-4.62 (m, 0.5H), 4.51-4.47(m, 0.5H), 4.06-4.03 (m, 0.5H), 3.95-3.92 (m, 1H), 3.82 (s, 3H),3.69-3.64 (m, 1H), 3.63-3.51 (m, 0.5H), 3.08-3.04 (m, 0.5H), 2.17-2.06(m, 2H), 1.79-1.55 (m, 2H), 1.50-1.30 (m, 6H).

Example 92 Preparation of3-cyano-N-(1,4-dimethyl-3-((2S,4R)-2-methyl-1-((R)-3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Isolation of the second eluting peak from chiral SFC separation of thediastereomeric mixture described in Example 91, step 7 afforded thetitle compound (185 mg). LC/MS [M+H]=512.1. Chiral SFC: Rt=4.649 min(Method N). ¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.34-8.31 (m, 1H),8.15 (s, 1H), 8.01-7.98 (m, 1H), 7.79-7.75 (m, 1H), 7.25 (s, 1H),5.06-5.03 (m, 0.5H), 4.85-4.83 (m, 1H), 4.66-4.62 (m, 0.5H), 4.51-4.47(m, 0.5H), 4.06-4.03 (m, 0.5H), 3.95-3.92 (m, 1H), 3.82 (s, 3H),3.69-3.64 (m, 1H), 3.63-3.51 (m, 0.5H), 3.08-3.04 (m, 0.5H), 2.17-2.06(m, 2H), 1.79-1.55 (m, 2H), 1.50-1.30 (m, 6H).

Examples 93-94 & 113

The following Examples 93-94 and 113 were prepared analogous to Example91 employing 3-cyano-4-methoxybenzoic acid in Step 5. Chiral SFCseparation (ChiralCel AS, 250×30 mm, 5 μm, CO₂/IPA-NH₃H₂O, 60/40, 50mL/min) of the resulting diastereomers afforded Example 93 as the firsteluting isomer and Example 94 as the second eluting isomer.

Ex. Structure Name/Characterization 93

3-cyano-N-(1,4-dimethyl-3-((2S,4R)-2-methyl-1-((S)-3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] = 542.2.Chiral SFC: Rt = 9.21 min (Method O). ¹H NMR (400 MHz, CD₃OD) δ 8.34-8.31 (m, 2H), 8.12 (s, 1H), 7.38-7.35 (m, 1H), 7.23 (s, 1H), 5.04-5.02(m, 0.5H), 4.73-4.50 (m, 2H), 4.09 (s, 3H), 4.01-3.97 (m, 1H), 3.82 (s,3H), 3.73-3.46 (m, 2H), 3.17-3.13 (m, 0.5H), 2.66 (s, 3H), 2.17-2.06 (m,2H), 1.75-1.02 (m, 8H). 94

3-cyano-N-(1,4-dimethyl-3-((2S,4R)-2-methyl-1-((R)-3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] = 542.2.Chiral SFC: Rt = 9.65 min (Method O). ¹H NMR (400 MHz, CD₃OD) δ 8.34-8.31 (m, 2H), 8.12 (s, 1H), 7.38-7.35 (m, 1H), 7.23 (s, 1H), 5.04-5.02(m, 0.5H), 4.73-4.50 (m, 2H), 4.09 (s, 3H), 4.01-3.97 (m, 1H), 3.82 (s,3H), 3.73-3.46 (m, 2H), 3.17-3.13 (m, 0.5H), 2.66 (s, 3H), 2.17-2.06 (m,2H), 1.75-1.02 (m, 8H). 113

3-cyano-N-(3-((2S,4R)-1-isobutyryl-2-methylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide. 1H NMR (400MHz, CDCl3) δ 8.34 (s, 1 H), 8.27-8.26 (m, 2 H), 8.20 (s, 1H), 7.85 (d,J = 7.7 Hz, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 6.92 (s, 1 H), 4.22 (br s,1 H), 3.94 (br s, 1 H), 3.83 (s, 3 H), 3.30-2.96 (m, 2 H), 2.80 (p, J =6.7 Hz, 1 H), 2.54 (s, 3H), 2.26 (d, J = 11.8 Hz, 1 H), 1.99 (s, 1 H),1.62-1.53 (m, 2 H), 1.20-1.06 (m, 9H).

Example 95

Example 95 was prepared analogous to Example 90 employing1-methyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(prepared as described in Example 65, step 1) in Step 3 and isobutyrylchloride in step 7.

Ex. Structure Name/Characterization 95

3-cyano-N-(3-((2S,4R)-1-isobutyryl-2-methylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. LC/MS [M + H] = 512.1; ¹H NMR (400 MHz, CD₃OD)δ 8.36-8.29 (m, 3H), 8.01- 7.99 (m, 1H), 7.79-7.75 (m, 1H), 7.68-7.65(m, 1H), 5.02-4.99 (m, 0.5H), 4.65-4.62 (m, 0.5H), 4.45-4.50 (m, 0.5H),4.07-4.03 (m, 0.5H), 3.92 (s, 3H), 3.57-3.52 (m, 1H), 3.40-3.39 (m,0.5H), 3.03-2.98 (m, 1.5H), 2.03- 1.92 (m, 2H), 1.73-1.55 (m, 2H),1.43-1.23 (m, 3H), 1.18-0.95 (m, 6H).

Example 96 Preparation of3-cyano-N-(3-(4-isobutyryl-4-azaspiro[2.5]octan-7-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1: ethyl 3-((1-(2-ethoxy-2-oxoethyl)cyclopropyl)amino)propanoate.Cyclopropylidene ethyl ester (500 mg, 3.96 mmol), ethyl3-aminopropanoate hydrochloride salt (1.22 g, 7.93 mmol) and DIPEA (2.76mL, 15.9 mmol) were loaded into a microwave vial and dissolved in THF (8mL). The mixture was heated to 100° C. for 60 min. An NH₄Cl solution andDCM were added and the phases were separated. The organic layer wasconcentrated and the residue was purified by silica gel columnchromatography (heptane/EtOAc, 1:1) to provide the title compound (770mg, 80%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 4.16 (q, J=7.3 Hz,2H), 4.12 (q, J=7.3 Hz, 2H), 2.93 (t, J=6.6 Hz, 2H), 2.44 (m, 4H), 1.27(t, J=7.3 Hz, 3H), 1.25 (t, J=7.3 Hz, 3H), 0.69 (m, 2H), 0.48 (m, 2H).

Step 2: ethyl 7-oxo-4-azaspiro[2.5]octane-6-carboxylate. To a solutionof ethyl 3-((1-(2-ethoxy-2-oxoethyl)cyclopropyl)amino)propanoate (310mg, 1.27 mmol) in THF (8 mL) was added KOtBu (572 mg, 5.10 mmol) at 0°C. The mixture was stirred for 60 min at 0° C. and then at roomtemperature for 30 min, whereupon dilute NH₄Cl solution and DCM wereadded. The organic layer was separated and concentrated in vacuo toprovide the title compound (150 mg, 60%) as a light yellow oil. Thecrude product was used in the subsequent step without furtherpurification. ¹H NMR (500 MHz, CDCl₃) δ 4.21 (m, 2H), 3.75-1.84 (m, 5H),1.29 (m, 3H), 0.90-0.47 (m, 2H), 0.75-0.67 (m, 2H)

Step 3: 4-azaspiro[2.5]octan-7-one. A solution of ethyl7-oxo-4-azaspiro[2.5]octane-6-carboxylate (250 mg, 1.27 mmol) inacetonitrile/water (9:1, 4 mL) was heated to 140° C. under microwaveirradiation for 3 h. Evaporation of the volatiles in vacuo provided thetitle compound (105 mg, 66%) as an orange oil. The crude product wasused in the subsequent step without further purification. ¹H NMR (500MHz, CDCl₃) δ 3.19 (m, 2H), 2.39 (m, 2H), 2.30 (s, 2H), 0.67 (m, 2H),0.47 (m, 2H).

Step 4: tert-butyl 7-oxo-4-azaspiro[2.5]octane-4-carboxylate.4-azaspiro[2.5]octan-7-one (105 mg, 0.839 mmol) was dissolved in DCM (5mL). TEA (234 μL, 1.68 mmol), DMAP (10 mg, 0.084 mmol) and Boc₂O (366mg, 1.68 mmol) were added and the mixture was stirred for 18 h at roomtemperature. A NaHCO₃ solution and DCM were added and the phases wereseparated. The organic layer was concentrated and the residue waspurified by silica gel column chromatography (heptane/EtOAc,90:10-80:20) to provide the title compound (50 mg, 26%) as a colorlessoil. ¹H NMR (500 MHz, CDCl₃) δ 3.70 (t, J=6.0 Hz, 2H), 2.43 (t, J=6.0Hz, 2H), 2.32 (s, 2H), 1.49 (s, 9H), 0.95 (m, 2H), 0.70 (m, 2H).

Step 5: tert-butyl7-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4-carboxylate.To a solution of tert-butyl 7-oxo-4-azaspiro[2.5]octane-4-carboxylate(50 mg, 0.222 mmol) in THF (2 mL) at −78° C. was added KHMDS (0.53 mL,0.266 mmol, 0.5 M solution in toluene). After 30 min at −78° C., triflicanhydride (56 μL, 0.333 mmol) was added. The mixture was stirred for 30min at −78° C. and 1 h at 0° C. A NaHCO₃ solution and DCM were added,and the phases were separated. The organic layer was concentrated invacuo. The residue was purified by silica gel column chromatography(heptane/EtOAc, 9:1) to provide the title compound (59 mg, 73%) as acolorless oil. ¹H NMR (500 MHz, CDCl₃) δ 5.87 (m, 1H), 4.07 (br s, 2H),2.35 (br s, 2H), 1.45 (s, 9H), 0.97 (br s, 2H), 0.76 (br s, 2H).

Step 6: tert-butyl7-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-azaspiro[2.5]oct-6-ene-4-carboxylate.A solution of1,4-dimethyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(prepared as described in Example 58, 52 mg, 0.162 mmol), tert-butyl7-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4-carboxylate(29 mg, 0.081 mmol), Pd(PPh₃)₄ (9.4 mg, 0.008 mmol) and a 2M solution ofK₃PO₄ in water (0.1 mL, 0.203 mmol) in dioxane (0.5 ml) was heated undermicrowave irradiation at 120° C. for 30 min. A NaHCO₃ solution and DCMwere added. The organic layer was concentrated. The residue was purifiedby silica gel column chromatography (heptane/EtOAc, 4:1) to provide thetitle compound (22 mg, 79%) as a solid. LC/MS [M+H]=399.

Step 7: tert-butyl7-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-azaspiro[2.5]octane-4-carboxylate.TEA (14 μL, 0.100 mmol) and Pd/C (10.2 mg, 0.005 mmol, 5% w/w) wereadded to a solution of tert-butyl7-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-azaspiro[2.5]oct-6-ene-4-carboxylate(20 mg, 0.050 mmol) in a mixture of MeOH:EtOAc (3 mL, 2:1). The mixturewas stirred under an atmosphere of hydrogen (1 bar) for 5 h. Thereaction mixture was filtered through a pad of Celite® eluting withEtOAc. The filtrate was concentrated in vacuo to afford the titlecompound. The crude product was used in the subsequent step withoutfurther purification. LC/MS [M+H]=371.

Step 8: tert-butyl7-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-azaspiro[2.5]octane-4-carboxylate.3-Cyanobenzoyl chloride (23 mg, 0.138 mmol) was added to a solution oftert-butyl7-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-azaspiro[2.5]octane-4-carboxylate(17 mg, 0.046 mmol) in pyridine (2 mL). The mixture was stirred at roomtemperature overnight and then concentrated in vacuo. The residue waspurified by silica gel column chromatography (heptane/EtOAc, 1:1-1:3) toprovide the title compound (12 mg, 52%) as a colorless oil. LC/MS[M+H]=500.

Step 9:3-cyano-N-(1,4-dimethyl-3-(4-azaspiro[2.5]octan-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.To a stirred solution of tert-butyl7-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-azaspiro[2.5]octane-4-carboxylate(12 mg, 0.024 mmol) in DCM (2 mL) was added TFA (89 μL, 1.20 mmol). Themixture was stirred at room temperature for 18 h. Saturated NaHCO₃solution was added and the mixture was extracted with DCM and EtOAc. Thecombined organic layers were washed with water and then concentrated invacuo to provide the title compound as a colorless oil, which was usedin the subsequent step without further purification.

Step 10:3-cyano-N-(3-(4-isobutyryl-4-azaspiro[2.5]octan-7-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.3-Cyano-N-(1,4-dimethyl-3-(4-azaspiro[2.5]octan-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamidewas dissolved in DCM (1 mL) and cooled to 0° C. TEA (7 μL, 0.048 mmol)and isobutyryl chloride (4 μL, 0.036 mmol) were added. The cooling bathwas removed and the mixture was stirred for 90 min at room temperature.A 1M HCl solution and DCM were added. The organic phase was separatedand concentrated in vacuo to provide the title compound (7 mg, 62% overtwo steps) as a white solid. LC/MS [M+H] 470; ¹H NMR (500 MHz, CDCl₃) δ8.34 (s, 1H), 8.25 (m, 1H), 8.19 (s, 1H), 7.84 (m, 1H), 7.64 (t, J=7.6Hz, 1H), 6.87 (s, 1H), 4.59-3.97 (m, 1H), 3.79 (s, 3H), 3.49 (m, 1H),3.30 (m, 1H), 2.87-2.74 (m, 1H), 2.56 (s, 3H), 2.10-1.91 (m, 2H),1.54-0.82 (m, 11H), 0.71-0.49 (m, 2H).

Example 97 Preparation ofrel-3-cyano-N-(3-((2S,4S,5S)-1-(cyclopentanecarbonyl)-2,5-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1:tert-butyl(3,6-trans)-3,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.To a solution of tert-butyltrans-2,5-dimethyl-4-oxopiperidine-1-carboxylate (J. B. Thomas et al. J.Med. Chem. 2001, 44, 972-987) (1.05 g, 4.62 mmol) in THF (30 mL) at −78°C. was added 1M solution of NaHMDS in THF (9.7 mL, 9.7 mmol). Themixture was stirred for 30 min., whereupon1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(3.5 g, 9.7 mmol) was added, and the reaction mixture was stirred at−78° C. for 30 min. The mixture was allowed to warm to room temperature.After 16 hr, the reaction mixture was concentrated in vacuo. The residuewas diluted with saturated ammonium chloride solution and extractedtwice with DCM. The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography (EtOAc:hexane, 2:98-4:96) to provide the titlecompound (1.2 g, 72%). ¹H NMR (400 MHz, CDCl₃) δ 5.70-5.65 (m, 1H),4.75-4.66 (m, 0.5H), 4.10-3.80 (m, 0.5H), 3.12-3.10 (m, 1H), 2.45-2.44(m, 1H), 1.78-1.63 (m, 1H), 1.47 (s, 2H), 1.47 (s, 9H), 1.21 (d, J=6.8Hz, 3H), 1.15 (d, J=6.8 Hz, 3H).

Step 2: tert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3,6-trans)-3,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate.To a solution of1,4-dimethyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(prepared as described in Example 58, 800 mg, 2.52 mmol) indioxane/water (18 mL:2 mL) was degassed with nitrogen for 30 min at roomtemperature in a seal tube.tert-butyl(3,6-trans)-3,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(996 mg, 2.78 mmol), K₃PO₄ (1.17 g, 5.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.02 mmol) were added and the resultingsolution was degassed for 15 min. The reaction mixture was sealed andheated at 105° C. for 2 h. The reaction mixture was cooled to roomtemperature and concentrated in vacuo. The residue was triturated withEtOAc and the solid obtained was filtered off. The filtrate was washedwith water. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The crude product was purified by silica gel columnchromatography (EtOAc:hexane, 10:90) to afford the title compound (820mg, 82%). ¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 7.05 (s, 1H),5.60-5.58 (m, 1H), 4.72-4.51 (m, 1H), 4.20-3.92 (m, 1H), 3.89 (s, 3H),3.24-3.16 (m, 1H), 2.81 (s, 3H), 2.38-2.37 (m, 1H), 1.51 (s, 9H), 1.24(d, J=6.4 Hz, 3H), 0.99 (d, J=6.4 Hz, 3H); LC/MS [M+CH₃CN]=442.

Step 3: tert-butyl4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,5-trans)-2,5-dimethylpiperidine-1-carboxylate.A solution of tert-butyl4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3,6-trans)-3,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate(800 mg, 1.9 mmol), 10% Pd/C (800 mg) and ammonium formate (1.3 g, 19.9mmol) in MeOH (50 mL) was heated at 80° C. for 24 h. The reactionmixture was cooled to room temperature, filtered through a pad ofCelite® and washed with EtOH. The filtrate was concentrated to providethe title compound (720 mg, 89%), which was used in the subsequent stepwithout further purification. LC/MS [M+H]=373; ¹H NMR (400 MHz, CDCl₃) δ7.98-7.86 (m, 1H), 6.74-6.73 (m, 1H), 4.68-4.43 (m, 1H), 4.20-3.92 (m,1H), 4.12-3.90 (m, 1H), 3.89 (s, 3H), 3.62-3.12 (m, 3H), 2.49 (s, 3H),2.25-1.98 (m, 2H), 1.48-1.45 (m, 9H), 1.40-1.02 (m, 3H), 0.65 (d, J=6.4Hz, 3H).

Step 4: tert-butyl4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,5-trans)-2,5-dimethylpiperidine-1-carboxylate.To a solution of tert-butyl4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,5-trans)-2,5-dimethylpiperidine-1-carboxylate(700 mg, 1.74 mmol) and TEA (0.7 mL, 5.22 mmol) in DCM (20 mL) at 0° C.was added 3-cyanobenzoyl chloride (347 mg, 2.1 mmol) in DCM (10 mL). Thereaction mixture was warmed to room temperature and stirred for 3 h. Thereaction mixture was diluted with DCM and extracted with 10% aqueousNaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated to provide the title compound (700 mg, 80%), which was usedin the next step without further purification. LC/MS [M+H]=502; ¹H NMR(400 MHz, CDCl₃): δ 8.27-8.19 (m, 3H), 7.86-7.84 (m, 2H), 7.64 (t, J=7.6Hz, 1H), 6.99-6.98 (m, 0.25H), 6.86-6.85 (m, 0.75H), 4.70-4.43 (m, 1H),3.99-3.85 (m, 1H), 3.82 (s, 3H), 3.70-3.15 (m, 2H), 2.62 (s, 3H),2.25-1.98 (m, 3H), 1.48-1.47 (m, 9H), 1.39-1.02 (m, 3H), 0.67-0.66 (m,3H).

Step 5:3-cyano-N-(3-(2,5-trans)-(2,5-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.To a solution of tert-butyl4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,5-trans)-2,5-dimethylpiperidine-1-carboxylate(700 mg, 1.39 mmol) in MeOH (5 mL) at 0° C. was added 4M HCl in dioxane(15 mL). The reaction mixture was allowed to warm to room temperatureand stir for 6 h. The mixture was concentrated in vacuo, and the residuewas washed with pentane to afford the title compound (600 mg, 99%).LC/MS [M+H]=402.

Step 6:rel-3-cyano-N-(3-((2S,4S,5S)-1-(cyclopentanecarbonyl)-2,5-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.To a solution of3-cyano-N-(3-(2,5-trans)-(2,5-dimethylpiperidin-4-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide(150 mg, 0.37 mmol) in DCM (5 mL) at 0° C. was added TEA (259 μL, 1.87mmol) and the mixture was stirred for 10 min. Cyclopentanecarbonylchloride (59 mg, 0.45 mmol) in DCM (1 mL) was added, and the mixture wasstirred for 3 h at room temperature. The reaction mixture was dilutedwith DCM and washed with 10% aqueous NaHCO₃ solution. The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by preparative HPLC to provide the title compound (85 mg,46%) as a white solid. LC/MS [M+H]=498.55; ¹H NMR (400 MHz, CD₃OD) δ8.40-8.38 (m, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.97 (t, J=8.0Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.33-7.32 (m, 0.25H), 7.17-7.16 (m,0.75H), 5.14-5.07 (m, 0.5H), 4.63-4.22 (m, 1.5H), 3.91-2.61 (m, 7H),3.16-3.06 (m, 2H), 2.63 (s, 3H), 2.30-2.23 (m, 2H), 1.92-1.62 (m, 6H),1.43-1.08 (m, 3H), 0.73 (d, J=6.8 Hz, 2H), 0.64 (d, J=6.8, 1H).

Example 98 Preparation of3-cyano-N-(3-((1R,5S,8r)-3-isobutyryl-3-azabicyclo[3.2.1]octan-8-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1. tert-butyl(8-anti)-[1-(4-bromo-2-fluoropyridin-3-yl)-2-nitroethyl]-3-azabicyclo[3.2.1]octane-3-carboxylate.At −78° C., 4-bromo-2-fluoropyridine (4.29 mmol, 0.455 mL) was slowlyadded to a solution of lithium diisopropylamide (2 M inTHF/heptane/ethylbenzyne, 4.29 mmol, 2.14 mL) in THF (4.29 mL). Themixture was stirred 1 h at −78° C. and tert-butyl(8-anti)-8-[(E)-2-nitroethenyl]-3-azabicyclo[3.2.1]octane-3-carboxylate(prepared as described in Example 77, step 5) (1.09 g, 3.86 mmol) in THF(4.29 mL) was slowly added. The mixture was stirred 30 min at −78° C.and then the cold bath was removed. The mixture was stirred until itreached room temperature and was then quenched with a saturated solutionof NH₄Cl (5 mL). The aqueous phase was extracted several times with DCM(5 mL). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and evaporated. The crude product waspurification by flash chromatography (heptane:AcOEt, 100/0-40/60) toprovide the title compound (912 mg, 52%) as a yellow solid. LC/MS[M−Me+H]=445.0; ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=5.3 Hz, 1H), 7.45(d, J=5.1 Hz, 1H), 4.67-4.85 (m, 2H), 4.04 (d, J=14.0 Hz, 0.5H),3.81-3.95 (m, 3H), 3.72 (d, J=12.9 Hz, 0.5H), 2.66-2.96 (m, 2H),2.11-2.28 (m, 2H), 1.80-2.02 (m, 2H), 1.71 (m, 2H), 1.45 (br. s., 9H).

Step 2.(8-anti)-[1-(4-bromo-2-fluoropyridin-3-yl)-2-nitroethyl]-3-azabicyclo[3.2.1]octane-3-carboxylate.At 25° C., a solution of HCl (4M in dioxane, 4.97 mL, 19.9 mmol) wasslowly added to a solution of tert-butyl(8-anti)-[1-(4-bromo-2-fluoropyridin-3-yl)-2-nitroethyl]-3-azabicyclo[3.2.1]octane-3-carboxylate(912.0 mg, 1.99 mmol) in DCM (6.63 mL). The reaction mixture was stirredfor 1 h at 50° C. The solvent was directly removed under reducedpressure, providing the hydrochloride salt of the title compound (785mg, 100%) which was dried over 1 h under high vacumn. LC/MS [M+H]=358.0;¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=5.5 Hz, 1H), 7.62 (d, J=5.5 Hz,1H), 5.01 (dd, J=12.9, 4.7 Hz, 1H), 4.85-4.95 (m, 2H), 3.98 (td, J=10.1,4.7 Hz, 1H), 3.20-3.29 (m, 2H), 3.03-3.16 (m, 2H), 2.54-2.59 (m, 1H),2.45-2.51 (m, 1H), 2.12-2.33 (m, 2H), 1.82-1.92 (m, 1H), 1.70-1.82 (m,2H).

Step 3.1-{(8-anti)-[1-(4-bromo-2-fluoropyridin-3-yl)-2-nitroethyl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one.At room temperature, a saturated solution of NaHCO₃ (18.0 mL) was addedto a solution of tert-butyl(8-anti)-[1-(4-bromo-2-fluoropyridin-3-yl)-2-nitroethyl]-3-azabicyclo[3.2.1]octane-3-carboxylatehydrochloride (785 mg, 1.99 mmol) in DCM (6.63 mL). The mixture wasstirred vigorously and isobutyryl chloride (230 μL, 2.19 mmol) wasslowly added. After 10 min, the mixture was transferred to a separatingfunnel and the phases were separated. The aqueous layer was extractedtwice with DCM (5 mL) and the combined organic layers were dried withsodium sulfate, filtered, and evaporated to provide the title compound(819 mg, 97% yield). LC/MS [M+H]=428.0; (Note: ¹H NMR complex due to thepresence of rotamers and diastereomers). ¹H NMR (400 MHz, CDCl₃) δ 7.99(d, J=5.1 Hz, 1H), 7.46 (d, J=5.1 Hz, 1H), 4.69-4.86 (m, 2H), 4.49 (d,J=13.7 Hz, 0.5H), 4.32 (d, J=13.7 Hz, 0.5H), 3.93 (t, J=11.1 Hz, 1H),3.81 (d, J=12.9 Hz, 0.5H), 3.64 (d, J=11.7 Hz, 0.5H), 3.21 (d, J=11.9Hz, 0.5H), 3.08 (d, J=12.9 Hz, 0.5H), 2.66-2.84 (m, 1.5H), 2.57 (d,J=13.3 Hz, 0.5H), 2.32-2.21 (m, 2H), 2.03-1.78 (m, 2H), 1.75-1.43 (m,4H), 1.20-1.02 (m, 6H).

Step 4.1-[(8-anti)-(4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one.At room temperature, AcOH (1.11 mL, 19.4 mmol) and zinc powder (1.27 g,19.4 mmol) were successively added to a solution of1-{(8-anti)-[1-(4-bromo-2-fluoropyridin-3-yl)-2-nitroethyl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one(819 mg, 1.94 mmol) in THF (3.87 mL). The mixture was stirred overnightat room temperature. The mixture was filtered through a plug of Celite®and rinsed with DCM. The filtrate was concentrated and the residue waspurification by silica gel column chromatography (DCM:MeOH, 100/0-85/15)to afford the title compound (268 mg, 37% yield) as a white powder whichwas immediately used in the next step.

Step 5.1-[(8-anti)-(4-bromo-1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one.At room temperature, to a solution of1-[(8-anti)-(4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one(268 mg, 0.708 mmol) in THF (2.36 mL) was added in one portion NaH (60%in oil, 57 mg, 1.42 mmol) followed by methyl iodide (49 uL, 0.78 mmol).The reaction was stirred for 2 h and was then quenched with a saturatedsolution of NH₄Cl (5 mL) and diluted with DCM (5 mL). The phases wereseparated and the aqueous layer was extracted twice with DCM (5 mL). Thecombined organic layers were dried over Na₂SO₄, filtered and evaporated.The crude product was purification by silica gel column chromatography(heptane:EtOAc, 100/0-0/100) to afford the title compound (123 mg, 44%yield) as a colorless oil. LC/MS [M+H]=392.1; ¹H NMR (400 MHz, CDCl₃) δ7.73 (d, J=5.9 Hz, 1H), 6.68-6.60 (m, 1H), 4.49-4.41 (m, 0.6H),4.39-4.31 (m, 0.4H), 3.82-3.74 (m, 0.4H), 3.73-3.65 (m, 0.6H), 3.47-3.30(m, 2H), 3.18 (d, J=12.1 Hz, 0.6H), 3.03-2.74 (m, 5.4H), 2.69 (d, J=12.5Hz, 0.6H), 2.52 (d, J=13.3 Hz, 0.4H), 2.38-2.11 (m, 3H), 1.97-1.74 (m,2H), 1.71-1.41 (m, 2H), 1.21-1.02 (m, 6H).

Step 6.1-[(8-anti)-8-(4-bromo-1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one.At 0° C., to a solution of1-[(8-anti)-(4-bromo-1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one(123 mg, 0.313 mmol) in DCM (2.08 mL) were successively addedtrifluoroacetic acid (72 μL, 0.94 mmol), followed by tetramethylammoniumnitrate (128 mg, 0.94 mmol) and trifluoroacetic anhydride (131 μL, 0.94mmol). The mixture was stirred 1 h at 0° C. and 3 h at room temperature.The mixture was neutralized with a saturated solution of NaHCO₃ untilpH=8. The phases were separated and the aqueous layer was extractedthree times with DCM (5 mL). The combined organic layers were dried withNa₂SO₄, filtered, and concentrated to afford the title compound (135 mg,99% yield) as a yellow powder which was used immediately for the nextstep.

Step 7.1-[(8-anti)-8-(4-methyl-1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one.At room temperature, dimethylzinc (17.0 mg, 0.178 mmol) was added to asolution of1-[(8-anti)-8-(4-bromo-1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one(31.0 mg, 0.071 mmol) in dioxane (0.475 mL). The reaction was thenheated to 80° C. in a microwave vessel for 90 minutes and then cooled toroom temperature. The mixture was then treated with a saturated solutionof NH₄Cl until pH=6. The phases were separated and the aqueous layer wasextracted three times with DCM (5 mL). The combined organic phases weredried over Na₂SO₄, filtered, and evaporated. The crude product waspurified by flash chromatography (DCM:EtOAc, 100/0-0/100) to provide thetitled compound (10 mg, 38% yield) as a white powder. LC/MS [M+H]=372.0;¹H NMR (400 MHz, CDCl₃) δ 1.14 (d, J=7.0 Hz, 3H), 1.21 (d, J=7.0 Hz,3H), 1.21-1.30 (m, 2H), 1.79 (m, 2H), 2.57 (br. s., 2H), 2.87 (spt,J=7.0 Hz, 1H), 2.88 (s, 3H), 2.92 (d, J=14.0 Hz, 1H), 3.32 (s, 1H), 3.41(d, J=11.7 Hz, 1H), 3.86 (m, 1H), 4.11 (s, 3H), 4.53 (d, J=12.9 Hz, 1H),6.92 (s, 1H), 8.91 (s, 1H).

Step 8.1-[(8-anti)-8-(5-amino-4-methyl-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one.At room temperature, to a solution of1-[(8-anti)-8-(4-methyl-1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one(20 mg, 0.052 mmol) in mixture of methanol/THF (1:1, 1.73 mL) was addeda saturated solution of NH₄Cl (0.450 mL) followed by zinc dust (17 mg,0.259 mmol). The resulting gray mixture was stirred at room temperaturefor 10 min and was filtered through a fritted plastic funnel and thefilter cake was rinsed with DCM and water. The phases were separated andthe aqueous layer was extracted three times with DCM (5 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated to provide the title compound (18 mg, 90%) which was usedimmediately in the next step. LC/MS [M+H]=341.2.

Step 9.3-cyano-N-(3-(3-isobutyryl-3-azabicyclo[3.2.1]octan-8-yl)-4-methyl-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.At room temperature, to a solution of1-[(8-anti)-8-(5-amino-4-methyl-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.2.1]oct-3-yl]-2-methylpropan-1-one(18 mg, 0.050 mmol) in DCM (0.505 mL) were successively addeddiisopropylethylamine (DIEA, 0.076 mmol, 13.3 μL) and 3-cyanobenzoylchloride (10.9 mg, 0.066 mmol). The mixture was stirred for 30 min andthen was quenched with a saturated solution of NaHCO₃ (5 mL). The phaseswere separated and the aqueous layer was extracted three times with DCM(5 mL). The combined organic phases were dried with sodium sulfate,filtered, and concentrated. The crude product was purification by silicagel column chromatography (DCM:EtOAc, 0/100-0/100) to give the titlecompound (16.5 mg) as a white powder. LC/MS [M+H]=470.2; ¹H NMR (400MHz, CDCl₃) δ 8.58 (br. s., 1H), 8.52-8.50 (m, 2H), 7.87-7.86 (m, 1H),7.64-7.73 (m, 1H), 7.02 (br. s., 1H), 4.53-4.51 (m, 1H), 4.09 (br. s.,3H), 3.89-3.88 (m, 1H), 3.42-3.41 (m, 1H), 3.39 (b. s., 1H), 2.92-2.90(m, 1H), 2.85-2.80 (m, 1H), 2.78 (s, 3H), 2.47-2.57 (m, 2H), 1.80-1.89(m, 2H), 1.64-1.63 (m, 2H), 1.21-1.20 (m, 3H), 1.13-1.10 (m, 3H).

Example 99

The following Example 99 was prepared analogous to Example 98 howeveremploying the appropriate benzoic acid in Step 11 and the appropriatecarboxylic acid in step 8.

Ex. Structure Name/Characterization 99

3-cyano-N-(3-((1R,5S,8r)-3-(cyclopentanecarbonyl)-3-azabicyclo[3.2.1]octan-8-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methoxybenzamide. LC/MS [M + H] = 526.5;¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 8.25 (s, 1H), 7.73 (br. s., 1H),7.11 (m, 1H), 6.93 (s, 1 H), 4.49 (m, 1H), 4.04 (s, 3 H), 3.91 (m, 1H),3.83 (s, 3 H), 3.34-3.43 (m, 2 H), 2.87-2.99 (m, 2 H), 2.65 (s, 3 H),2.50 (br. s., 2 H), 1.75-1.94 (m, 12 H).

Example 100 Preparation of3-cyano-N-(3-((1R*,4S*,5R*)-2-(cyclopentanecarbonyl)-2-azabicyclo[2.2.2]octan-5-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1. tert-butyl5-(((trifluoromethyl)sulfonyl)oxy)-2-azabicyclo[2.2.2]oct-5-ene-2-carboxylate.A solution of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.44 g, 4.05 mmol) in THF (5 mL) was added to a solution of tert-butyl5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (760 mg, 3.37 mmol) in THF(15 mL) chilled to −78 C. The resulting mixture was warmed to roomtemperature and stirred over the course of 2 h. The mixture was thenconcentrated, brought up in DCM, and to this mixture was added aqNaHCO₃. The layers were separated and the aqueous layer was then washedthree times with DCM. The combined organic layers were concentratedunder reduced pressure and purified by silica gel column chromatography(heptane:EtOAc, 100:0-90:10) to give 1.07 g (89%) of the title compoundas a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 6.60-6.25 (m, 1H),5.00-4.50 (m, 1H), 3.40-3.25 (m, 2H), 3.00-2.75 (m, 1H), 2.10-2.00 (m,1H), 1.75-1.65 (m, 2H), 1.55-1.45 (m, 11H).

Step 2: tert-butyl5-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-azabicyclo[2.2.2]oct-5-ene-2-carboxylate.To a microwave vessel charged with tert-butyl5-(((trifluoromethyl)sulfonyl)oxy)-2-azabicyclo[2.2.2]oct-5-ene-2-carboxylate(500 mg, 1.40 mmol) was added sequentially1,4-dimethyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(prepared as in Example 58, step 1) (665 mg, 2.10 mmol), palladiumtetrakis(triphenylphosphine) (161 mg, 0.14 mmol), potassium phosphate(891 mg, 4.20 mmol), and p-dioxane (10 mL). The mixture was then bubbledwith argon and the vessel was then equipped with a stirbar and sealedand heated to 120° C. in a microwave for 30 minutes. After allowing tocool, the mixture was filtered through a pad of Celite® and the pad waswashed with DCM. The organic filtrates were then washed with 1N HClfollowed by water and then concentrated under reduced pressure. Thecrude residue was then purified by silica gel column chromatography(heptane:EtOAc, 80:20-50:50) to give 398 mg (87%) of the title compoundas a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 7.30-7.10 (m,1H), 6.55-6.45 (m, 1H), 4.95-4.60 (m, 1H), 3.97 (s, 3H), 3.47-3.40 (m,1H), 3.39-3.20 (m, 1H), 2.99-2.90 (m, 1H), 2.85 (s, 3H), 2.20-2.10 (m,1H), 1.80-1.30 (m, 12H).

Step 3: tert-butyl5-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate.To a microwave vessel charged with tert-butyl5-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-azabicyclo[2.2.2]oct-5-ene-2-carboxylatewas added ammonium formate (917 mg, 14.5 mmol) and 20% palladiumhydroxide on carbon (240 mg). The mixture was suspended in ethanol:water(3:1, 15 mL) and heated to 90° C. for 1 h. The mixture was then filteredthrough a pad of Celite® and the filtrate was concentrated to give 449mg (90%) of the title compound.

Step 4:N-(3-(2-azabicyclo[2.2.2]octan-5-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-cyanobenzamide.3-Cyanobenzoyl chloride (344 mg, 2.08 mmol) and pyridine (10 mL) wereadded to a round-bottomed flask charged with tert-butyl5-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate(514 mg, 1.39 mmol). The mixture was allowed to stir at 0° C. for 24 hand then was concentrated under reduced pressure. The crude residue wasbrought up in 1N HCl and extracted with DCM. The organic layer wasconcentrated and the crude residue was purified by silica gel columnchromatography (heptane:EtOAc, 50:50). The concentrated major fractionwas treated with DCM:TFA (9:1, 10 mL) and allowed to stir for 1 h. Themixture was concentrated under reduced pressure and treated with 1N NaOHand MeOH until the pH˜8. The mixture was extracted with DCM andconcentrated to give 399 mg (44%) of the title compound.

Step 5:3-cyano-N-(3-(2-(cyclopentanecarbonyl)-2-azabicyclo[2.2.2]octan-5-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide.Cyclopentanoyl chloride (66.8 mg, 0.5 mmol) and pyridine (3 mL) wereadded to a round-bottomed flask charged withN-(3-(2-azabicyclo[2.2.2]octan-5-yl)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-cyanobenzamide(100 mg, 0.25 mmol). The mixture was stirred at 0° C. for 1 h, and thenwas concentrated under reduced pressure. The crude residue was thenbrought up in 1N HCl and extracted with DCM. The organic layer wasconcentrated and the crude product was purified by HPLC to provide 50 mg(40%) of the title compound as a mixture of diastereomers. LCMS m/z[M+H]=496.3. ¹H NMR (400 MHz, CDCl₃) δ 8.40-8.35 (m, 1H), 8.34-8.28 (m,1H), 8.12 (s, 1H), 8.00-7.95 (m, 1H), 7.80-7.70 (m, 1H), 7.50-7.40 (m,1H), 4.60-4.15 (m, 1H), 3.95-3.65 (m, 5H),

Example 101 Assay of Co-Activator Recruitment by TR-FRET

The activity of compound of the invention can be determined by aco-activator recruitment by TR-FRET (time-resolved fluorescenceresonance energy transfer) assay. In general, the assay is based on theinteraction between N-terminally Six-Histidine-tagged-RORC2 ligandbinding domain (6-His-RORC2 LBD), expressed in E. coli and purified byaffinity chromatography, and biotin-coactivator peptide SRC1-2(biotin-aminohexanoic acid-CPSSHSSLTERHKILHRLLQEGSPS-NH₂; SEQ ID NO: 1)containing the LXXLL consensus domain which is responsible for receptorbinding. This interaction is detected by addition of Europiumlabeled-anti-His antibody (Ex. 337 nm, Em. 620 nm, which binds to 6His)and Streptavidin-APC (Ex. 620 nm, Em. 665 nm, which binds to biotin).When receptor and coactivator are bound to each other, upon shininglight at 337 nm on the sample, the Europium emits fluorescence thatexcites APC due to close proximity (FRET) and this signal is measured at665 nm. Due to the long lasting fluorescence emission of Europium, thenon-specific, short-lived fluorescence is time-resolved (TR) from thefluorescence of interest. Inhibitors of the interaction of receptor andcoactivator peptide are detected by a decrease in TR-FRET signal.

Specifically, in one embodiment the aforementioned assay was performedas outlined below. The assay was carried out in black polystyrene,384-well plates in a total assay volume of 50.5 μL. The assay buffercontained 50 mM TRIS—HCL pH 7.5, 1 mM NaCl, 2 mM MgCl₂, 0.5 mg/mL bovineserum albumin, and 5 mM dithiothreitol. The final concentration ofreagents was 6.3 nM RORC2 LBD, 200 nM SRC1-2, 50 nM streptavidin APC, 1nM Europium-labeled anti-His antibody, and varying concentrations ofcompounds such that final concentration of DMSO is 1% (v/v). The assaysteps were: (1) dispensing 500 μL compound at 100× final concentrationin DMSO (test wells) or DMSO only (control wells for no inhibition); and(2) dispensing 50 μL mixture of the other assay components includingreceptor (test wells) or excluding receptor (control wells for maximalinhibition).

Assay mixtures were incubated are room temperature for 3 hr and read inEnVision 2100 Multilabel Reader (PerkinElmer Life Sciences) atExcitation Filter 320, Emission Europium Filter 615, Emission APC Filter665, Dichroic Mirror D400/D630.

TR-FRET signal was determined by calculating the ratio of 665 nm by 615nm and IC₅₀ values of compounds of the invention (Table 1) weredetermined by the non-linear regression analysis of dose responsecurves.

References which relate to the above-referenced assay include: Kallen etal. Structure, 2002, 10, 1697-1707; Stehlin et al. EMBO J 2001, 20,5822-5831; and Zhou et al. Mol Endocrinol 1998, 12, 1594-1604.

TABLE 1 Example IC₅₀ (nM) 1 7.1 2 4.0 3 3.2 4 8.5 5 16.6 6 5.7 7 4.9 85.4 9 5.4 10 3.5 11 1.5 12 11.8 13 5.0 14 5.6 15 3.9 16 10.2 17 5.3 183.8 19 8.8 20 5.2 21 5.0 22 2.7 23 4.7 24 5.8 25 5.8 26 6.6 27 6.4 287.1 29 0.9 30 2.8 31 5.6 32 19.4 33 18.0 34 5.7 35 7.2 36 4.5 37 11.6 387.7 39 9.3 40 7.6 41 4.5 42 7.6 43 13.5 44 40.7 45 13.5 46 16.4 47 10.148 ND 49 6.2 50 7.5 51 6.9 52 13.7 53 8.5 54 4.7 55 10.6 56 5.6 57 11.758 15.0 59 11.8 60 15.4 61 15.2 62 9.7 63 12.9 64 41.8 65 5.7 66 7.4 678.7 68 9.7 69 10.2 70 5.6 71 9.8 72 15.3 73 22.6 74 6.2 75 7.3 76 7.5 775.2 78 2.1 79 39.1 80 4.3 81 1.2 82 5.1 83 28.8 84 14.4 85 40.9 86 16.087 15.0 88 26.0 89 31.0 90 21.2 91 26.9 92 16.5 93 32.9 94 39.4 95 2.796 24.3 97 18.6 98 102 99 21.1 100 23.0 109 26.8 110 9.5 111 18.4 11225.1 113 20.2 ND = not determined

Example 102 Assay of Gal4-RORC2 Activity by Luciferase Reporter

The activity of compound of the invention can be also be determined by aluciferase reporter Gal4-RORC2 activity assay. In general, Neuro2A cells(murine neuroblastoma cell line obtained from HPACC, cat #89121404) aretransiently transfected with a mammalian expression vector (pM)containing Gal4-RORC2 LBD and a Gal4-responsive reporter gene containingfirefly luciferase (5×GAL4UAS-Luc3). Gal4-RORC2 LBD is constitutivelyactive in the transfected Neuro2a cells, resulting in a robustluciferase response in the absence of stimulation. Upon treatment withan RORC2 inhibitor the transcriptional response is decreased and themagnitude of the decrease in response is dose-dependently related to theintrinsic efficacy of the inhibitor.

Specifically, the growth medium was composed by MEM EBS w/o L-glutamine,10% (v/v) FBS, 2 mM L-glutamine and 1× non-essential aminoacid (NEAA);the seeding medium was composed by MEM EBS w/o L-glutamine, w/o phenolred, 4% (v/v) FBS, 2 mM L-glutamine, 1×NEAA, 1% Penicillin (10,000U/mL)/Streptomycin (10,000 μg/mL); and the assay medium was composed byMEM EBS w/o L-glutamine, w/o phenol red, 4% (v/v) FBS, 2 mM L-glutamine,1×NEAA, 1% Penicillin (10,000 U/mL)/Streptomycin (10,000 μg/mL). Inaddition, Neuro2A cells were cultured in growth medium in humidifiedchambers at 37° C. and 5% CO₂ using standard tissue culture procedures.

On day one of the assay, cells were seeded and transfected.Specifically, Neuro2A cells were suspended in seeding medium and mixedwith plasmids and transfection reagent which was dissolved in OptiMEM Ireduced serum medium (InVitrogen), and then seeded to 384-well plates(Corning, Black, Clear bottom) in 40 μL/well containing 12,500 cells,17.25 ng Gal4-Luc3, 5.75 ng either empty pM vector (‘no receptorcontrol’ wells) or pM-Gal4RORgamma-LBD, and 0.11 μL Lipofectamine2000.

On day two of the assay, the cells were treated with compounds of theinvention. Specifically, the treatment was started 20-24 hr afterseeding and transfection of the cells. Compounds of the invention wereserially diluted in a 384-well polypropylene plate with assay mediumcontaining 0.5% (v/v) DMSO at 5× final assay concentration. 10 μL of thecompounds (or 0.5% DMSO in assay medium for ‘no compound control’ wells)were transferred from the dilution plate to the 384-format cell platesuch that final assay volume was 50 μL and final DMSO concentration was0.1% (v/v), followed by incubation for 20-24 hr in humidified chambersat 37° C. and 5% CO₂.

On day three of the assay, luminescence was measured and the resultsanalyzed. Specifically, 10 μL of SteadyLite Plus reagent (Perkin Elmer)was added to each well. The cell plates were incubated at roomtemperature for 15 min in the dark before reading of luminescence on theMicroBeta Trilux (Wallac). IC₅₀ values of the compounds tested weredetermined by the non-linear regression analysis of dose responsecurves.

References which relate to the above-referenced assay include:Stehlin-Gaon et al. Nature Structural Biology 2003, 10, 820-825; Wang etal. J Biol Chem. 2010, 285(7), 5013-5025; Kumar et al. Mol Pharmacol.2010, 77(2), 228-36.

Example 103 Assay of IL-17 Production from Human Th17 Cells

The activity of compound of the invention can be also be determined byan IL-17 production from human Th17 cells assay. In general, this assaymeasures blockade of IL-17 production, the signature cytokine of Thelper 17 (Th17) cells, by compounds. Purified human CD4+ T cells arestimulated with anti-CD3+ anti-CD28 and incubated with a cytokinecocktail that induce their differentiation into Th17 in the absence orpresence of various concentrations of compound. After 6 days, IL-17Aconcentration is measured in the cell culture supernatant with an ELISAkit (MSD).

Preparation of human CD4+ T cells. CD4+ T cells were purified from buffycoats from healthy donors (obtained from Massachusetts General Hospital)by negative selection the following procedure: Mixing 25 mL of bloodwith 1 mL of Rosette Sep CD4+ T cell enrichment cocktail (StemCellTechnologies) followed by application of a layer of 14 mL Ficoll PaquePlus (Amersham GE Healthcare) and subsequent centrifugation at 1200 gfor 20 min at room temperature. The Ficoll layer was then harvested andwashed with phosphate saline buffer containing 2% (v/v) fetal bovineserum and cells were resuspended with RPMI medium containing 10% (v/v)fetal bovine serum and 10% (v/v) DMSO, frozen and kept in LN2 untilused.

On the first day of the assay, a vial containing 10⁷ CD4+ T cells isthawed rapidly in 37° C. water bath, immediately transferred into 20 mLX-Vivo 15 medium (Lonza), is spun for 6 min at 300×g, the supernatant isdiscarded, and the resulting pellet is re-suspended at 10⁶ cells/mL in50 mL fresh X-Vivo 15 medium, followed by storage overnight in a tissueculture vessel in a humidified chamber at 37° C. and 5% CO₂. Serialdilutions of compounds of the invention are prepared at 10× finalconcentration in X-Vivo15 medium containing 3% (v/v) DMSO.

On the second day of the assay, a 384-well tissue culture plate wascoated with 10 μg/mL anti-hCD3 (eBioscience) at 50 μL/well. After 2 hrat 37° C., the supernatant is discarded and the coated plates are keptin a sterile tissue culture hood.

Cytokine plus anti-CD28 cocktail is prepared by mixing 25 ng/mL hlL-6(Peprotech), 5 ng/mL hTGFbeta1 (Peprotech), 12.5 ng/mL IL-1 beta(Peprotech), 25 ng/mL hlL-21, 25 ng/mL hlL-23 (R&D Systems), and 1 ug/mLanti-hCD28 (eBioscience) in X-Vivo 15 medium. The cytokine plusanti-CD28 cocktail with CD4+ cells is prepared such that the cocktail isdiluted 10-fold and cell density is 0.22×10⁶/mL. The mixture isincubated 1 hr at 37° C.

90 μL (20,000 cells) dispensed per well in the anti-hCD3 coated plateprepared as noted above.

10 μL 10× compound is added per well (final DMSO=0.3%) from the compoundplate that was previously prepared, followed by 6 days of incubation ina tissue culture vessel in a humidified chamber at 37° C. and 5% CO₂.

On day six of the assay, production of IL-17A in 10 μL of thesupernatant is determined by sandwich ELISA using 384 w hlL17 MSD platesfollowing the manufacturer's protocol. Measurement is carried out in aSector Imager 6000 by the same manufacturer. Signal units from theinstrument are converted to pg/mL using a calibration curve with knownamounts of IL-17A. IC₅₀ values of test compounds (Table 2) aredetermined by the non-linear regression analysis of dose responsecurves.

A reference which relates to the above-referenced assay is: Yang et al.Nature 2008, 454, 350-352.

TABLE 2 Example IC₅₀ (nM) 1 11.8 2 15.2 3 39.2 4 3.5 5 9.5 6 5.0 7 6.2 814.4 9 27.5 10 51.3 11 7.8 12 57.9 13 48.7 14 8.7 15 9.9 16 10.7 17 10.718 10.8 19 12.6 20 18.5 21 3.4 22 5.9 23 9.4 24 17.4 25 14.1 26 7.7 278.4 28 118 29 8.5 30 3.9 31 4.7 32 3.4 33 13.7 34 9.5 35 14.3 36 6.6 379.2 38 11.0 39 11.2 40 7.9 41 18.9 42 31.3 43 6.4 44 17.1 45 16.0 4657.4 47 8.4 48 13.4 49 8.0 50 3.4 51 6.4 52 12.0 53 121.4 54 5.0 55 6.056 4.9 57 36.4 58 9.3 59 9.9 60 15.0 61 25.6 62 15.8 63 12.0 64 10.2 6510.7 66 13.4 67 4.2 68 5.3 69 11.4 70 3.5 71 4.8 72 4.8 73 25.3 74 3.675 6.8 76 5.0 77 8.9 78 4.0 79 4.1 80 9.3 81 3.3 82 5.7 83 70.5 84 6.085 15.5 86 34.9 87 12.6 88 19.0 89 16.6 90 12.2 91 16.2 92 22.3 93 13.494 22.8 95 5.7 96 46.0 97 123.8 98 276 99 14.7 100 10.4 109 32.1 11024.7 111 24.2 112 36.0 113 29.8

Example 104 Inhibition of Superantigen-Induced Th17 Cytokine Production

Exotoxins called “superantigens” are among the most powerful T cellactivators. Superantigens bind to the cell surface of majorhistocompatibilty complex (MHC) molecules, without intracellularprocessing. They stimulate T cells via the T cell receptor, irrespectiveof the antigen specificities. Therefore, bacterial superantigens areable to activate a large pool of CD4+ as well as CD8+ T cells incontrast to the low T cell frequency for conventional antigens. CD4+ Tcells can be classified into various subsets (Th0, Th1, Th2, Th17) basedon their respective cytokine secretion profiles. Th0 cells areuncommitted naïve precursor cells that primarily produce IL-2 uponstimulation. Th0 cells upon activation can differentiate into Th1, Th2,or the Th17 subset depending on the local cytokine milieu. Th1 cellsmainly produce Inf-γ; Th2 cells, IL-4, IL-5, and IL-13, and Th17 cells,IL-17, and IL-22. During a classical immune response, thedifferentiation of T helper subset occurs over days, or longer. In thesuperantigen in-vivo model in mice injection of superantigen triggers arapid transcription and translation of the various cytokines (i.e. IL-2,IL-4, Inf-γ, IL-17) of the different Th subsets after only 6 hr. A RORγtinhibitor given to animals prior to the superantigen stimulus wouldimpair the Th17 cytokine profile without affecting the cytokine profileof the other Th subsets (Th0, Th1, Th2). The model uses approximately 8week old C57BL/6, Balb/c, or C3H/HeJ mice which are dosed orally withcompound 1 to 2 hr prior to superantigen injection on the day of theexperiment (Day 0) based on the pharmacokinetic (PK) profile of thecompound. An optional dose may be given the day before superantigeninjection (Day −1) to further inhibit the response if necessary. C57BL/6and Balb/c mice will be sensitized 1 hr prior to supernatigen injectionwith approximately 25 mg/mouse D-Galactosamine intraperitoneally(C3H/HeJ mice do not need to be sensitized). Based on the literaturesuperantigen is typically given at 10 μg/mouse intraperitoneally. Micewill be sacrificed at 3 hr for RNA analysis or up to 6 hr for cytokineanalysis.

A reference which relates to the above-referenced assay is: Rajagopalan,G. et. al. Physiol Genomics 2009, 37, 279.

Example 105 Imiquimod Assay

Commercially available 5% imiquimod (IMQ) cream (3M Pharmaceuticals) isapplied to the back and right ear of each experimental mouse for twoconsecutive days. Control mice are treated similarly with a commerciallyavailable vehicle cream. The experimental mice are then administeredwith RORγt inhibitors, and the control mice with vehicle, for 4 days.The ear thickness is measured on all days by digital micrometer(Mitutoyo). Tissues, such as ears and speens, are harvested on Day 5 forRNA analysis. Ear swelling and serum measurements are also made.

References describing aspects of this assay include: Van der Fits, L. etal. J. Immunol. 2009, 182(9), 5836-45; Van Belle, A. B. et al. JImmunol. 2012, 188(1), 462-9; Cai, Y. et al. Immunity 2011, 35(4),596-610; Fanti, P. A. et al. Int. J. Dermatol. 2006, 45(12), 1464-5;Swindell, W. R. et al. PLoS One 2011, 6(4), e18266; and Roller, A. etal. J. Immunol. 2012, 189(9), 4612-20.

Example 106 IL-23 Injection Model of Mouse Skin Inflammation

Ears from BALB/c mice were each injected intra-dermally every other daywith 150 ng of mouse recombinant IL-23 (eBiosciences) or PBS in a totalvolume of 25 μl. Ear swelling was measured in triplicate using amicrometer (Mitutoyo) right before each IL-23 challenge. On Day 14, micewere euthanized and ears were collected for measurement of cytokinelevels, gene expression levels and hystopathological evaluation. Micewere administered 3-100 mg/kg of an RORC2 modulator or vehicle oncedaily orally for the duration of the study. Alternatively, the RORC2modulator was applied topically once or twice daily using a standardformulation (EtOH:propylene glycol:dimethyl isosorbide:DMSO,38:30:15:15) at a concentration of 0.1% to 5.0%.

References describing aspects of this assay include: Muramoto, K. et al.J. Pharmacol. Exp. Ther. 2010, 335(1), 23-31; Fridman, J. S. et al. J.Invest. Dermatol. 2011, 131(9), 1838-1844.

Example 107 Single Crystal X-Ray Analysis of1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one

1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-oneis the product of step 11 of Example 56. A crystal suitable for X-rayanalysis was prepared by recrystallization from ethyl acetate.

Data collection was performed on a Bruker APEX diffractometer at roomtemperature. Data collection consisted of omega and psi scans.

The structure was solved by direct methods using SHELX software suite inthe space group P2_(1/n). The structure was subsequently refined by thefull-matrix least squares method. All non-hydrogen atoms were found andrefined using anisotropic displacement parameters.

The hydrogen atoms located on nitrogen was found from the Fourierdifference map and refined with distances restrained. The remaininghydrogen atoms were placed in calculated positions and were allowed toride on their carrier atoms. The final refinement included isotropicdisplacement parameters for all hydrogen atoms.

The final R-index was 6.6%. A final difference Fourier revealed nomissing or misplaced electron density.

FIG. 1 is an ORTEP Drawing of1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one.Pertinent crystal, data collection and refinement are summarized inTable 3. Atomic coordinates, bond lengths, bond angles, torsion anglesand displacement parameters are listed in Tables 4-7.

TABLE 3 Crystal data and structure refinement for 1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one. CrystallizationEtOAc Empirical Formula C20 H25 F3 N4 O Formula weight 394.44Temperature 296(2) K Wavelength 1.54178 Å Crystal system MonoclinicSpace group P2(1)/n Unit cell dimensions a = 12.2804(3) Å; α = 90°. b =10.7277(3) Å; β = 101.714(2)°. c = 14.7594(4) Å; γ = 90°. Volume 1903.91(9) Å³ Z 4 Density (calculated) 1.376 Mg/m³ Absorption coefficient 0.904mm⁻¹ F(000) 832 Crystal size 0.18 × 0.16 × 0.04 mm³ Theta range for datacollection 4.28 to 54.22°. Index ranges −11 <= h <= 12, −10 <= k <= 11,−14 <= l <= 11 Reflections collected 6183 Independent reflections 1992[R(int) = 0.0573] Completeness to theta = 54.22° 86.1% Absorptioncorrection Empirical Max. and min. transmission 0.9647 and 0.8542Refinement method Full-matrix least-squares on F²Data/restraints/parameters 1992/2/265 Goodness-of-fit on F² 1.185 FinalR indices [I > 2sigma(I)] R1 = 0.0661, wR2 = 0.1767 R indices (all data)R1 = 0.0912, wR2 = 0.2093 Extinction coefficient 0.0038(7) Largest diff.peak and hole 0.266 and −0.310 e.Å⁻³

TABLE 4 Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for 1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one. U(eq) is defined as onethird of the trace of the orthogonalized U^(ij) tensor. x y z U(eq) C(1)2026(4) −1414(6)  114(3) 62(2) C(2) 2266(4) −2663(6)  418(3) 67(2) C(3)1526(5) −3574(7)  26(4) 75(2) C(4)  544(5) −3232(8) −596(4) 83(2) C(5)1026(4) −1236(6) −544(3) 64(2) C(6) 3309(5) −2950(7) 1082(4) 77(2) C(7)1809(4)  614(6) −293(3) 62(2) C(8) 2525(4)  −182(5)  264(3) 58(2) C(9) −20(4)  541(6) −1438(3)  79(2) C(10) 3606(4)  206(5)  904(3) 60(2)C(11) 3489(4)  677(6) 1859(3) 65(2) C(12) 4629(4)  672(6) 2500(3) 67(2)C(13) 5410(4)  1297(6) 1122(3) 63(2) C(14) 4210(4)  1324(6)  591(3)60(2) C(15) 3617(5)  2463(7)  877(4) 81(2) C(16) 3072(5)  2007(7)1658(4) 85(2) C(17) 6402(4)  1731(5) 2726(4) 63(2) C(18) 7343(4) 2286(6) 2340(3) 70(2) C(19) 8456(4)  2140(7) 3013(4) 97(2) C(20)7118(5)  3659(7) 2119(4) 94(2) F(1) 4207(3) −2855(4)  709(2) 105(1) F(2) 3498(3) −2182(3) 1811(2) 91(1) F(3) 3344(3) −4078(4) 1467(3)116(2)  N(1) 1645(5) −4865(6)  225(4) 100(2)  N(2)  281(4) −2101(6)−900(3) 78(2) N(3)  907(3)   −3(5) −782(3) 67(1) N(4) 5468(3)  1358(4)2124(2) 60(1) O(1) 6462(3)  1642(4) 3571(2) 76(1)

TABLE 5 Bond lengths [Å] and angles [°] for 1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one. C(1)—C(5)1.415(6) N(2)—C(4)—C(3) 125.7(6) C(1)—C(2) 1.425(8) N(2)—C(5)—N(3)122.8(5) C(1)—C(8) 1.455(8) N(2)—C(5)—C(1) 127.3(6) C(2)—C(3) 1.379(8)N(3)—C(5)—C(1) 109.9(5) C(2)—C(6) 1.479(7) F(1)—C(6)—F(3) 106.8(6)C(3)—C(4) 1.408(8) F(1)—C(6)—F(2) 105.2(5) C(3)—N(1) 1.417(8)F(3)—C(6)—F(2) 103.3(5) C(4)—N(2) 1.311(8) F(1)—C(6)—C(2) 112.9(5)C(5)—N(2) 1.335(7) F(3)—C(6)—C(2) 114.8(5) C(5)—N(3) 1.368(7)F(2)—C(6)—C(2) 113.0(6) C(6)—F(1) 1.332(7) N(3)—C(7)—C(8) 111.5(5)C(6)—F(3) 1.334(7) C(7)—C(8)—C(1) 106.0(4) C(6)—F(2) 1.338(7)C(7)—C(8)—C(10) 125.0(5) C(7)—N(3) 1.365(6) C(1)—C(8)—C(10) 129.0(5)C(7)—C(8) 1.373(7) C(8)—C(10)—C(14) 116.2(4) C(8)—C(10) 1.522(6)C(8)—C(10)—C(11) 115.4(4) C(9)—N(3) 1.458(6) C(14)—C(10)—C(11)  99.2(4)C(10)—C(14) 1.531(7) C(12)—C(11)—C(16) 110.8(5) C(10)—C(11) 1.531(7)C(12)—C(11)—C(10) 109.0(4) C(11)—C(12) 1.522(6) C(16)—C(11)—C(10)102.8(4) C(11)—C(16) 1.524(8) N(4)—C(12)—C(11) 113.0(4) C(12)—N(4)1.465(6) N(4)—C(13)—C(14) 111.2(4) C(13)—N(4) 1.468(6) C(13)—C(14)—C(15)109.9(4) C(13)—C(14) 1.522(6) C(13)—C(14)—C(10) 107.9(4) C(14)—C(15)1.525(8) C(15)—C(14)—C(10) 104.9(5) C(15)—C(16) 1.528(8)C(14)—C(15)—C(16) 105.0(5) C(17)—O(1) 1.237(6) C(11)—C(16)—C(15)105.3(5) C(17)—N(4) 1.360(6) O(1)—C(17)—N(4) 120.4(5) C(17)—C(18)1.512(8) O(1)—C(17)—C(18) 121.1(4) C(18)—C(20) 1.522(9) N(4)—C(17)—C(18)118.5(4) C(18)—C(19) 1.526(6) C(17)—C(18)—C(20) 110.0(5) C(5)—C(1)—C(2)116.0(5) C(17)—C(18)—C(19) 111.4(5) C(5)—C(1)—C(8) 105.1(5)C(20)—C(18)—C(19) 109.8(5) C(2)—C(1)—C(8) 138.8(4) C(4)—N(2)—C(5)114.0(5) C(3)—C(2)—C(1) 117.3(5) C(7)—N(3)—C(5) 107.4(4) C(3)—C(2)—C(6)122.6(6) C(7)—N(3)—C(9) 126.6(5) C(1)—C(2)—C(6) 120.0(5) C(5)—N(3)—C(9)125.9(4) C(2)—C(3)—C(4) 119.5(7) C(17)—N(4)—C(12) 117.7(4)C(2)—C(3)—N(1) 125.0(5) C(17)—N(4)—C(13) 122.3(4) C(4)—C(3)—N(1)115.4(6) C(12)—N(4)—C(13) 117.7(4)

TABLE 6 Anisotropic displacement parameters (Å² × 10³) for1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan- 1-one. Theanisotropic displacement factor exponent takes the form: −2π²[h²a*²U¹¹ + . . . + 2 h k a* b* U¹²]. U¹¹ U²² U³³ U²³ U¹³ U¹² C(1) 27(3)122(5) 35(3) −7(3) −4(2)  −6(3) C(2) 37(3) 112(5) 46(3) −3(3) −5(3) −6(3) C(3) 55(4) 112(5) 56(3) −8(3)  6(3)  −3(4) C(4) 56(4) 125(6)62(4) −16(4)   0(3) −24(4) C(5) 33(3) 111(5) 43(3) −5(3) −2(2)  −3(3)C(6) 59(4) 113(6) 52(4) 14(4) −6(3)  −3(4) C(7) 34(3) 100(4) 48(3) −4(3)−6(3)  −7(3) C(8) 28(3) 102(4) 39(3) −8(3) −6(2)  −5(3) C(9) 38(3)132(5) 56(3)  5(3) −14(3)   4(3) C(10) 29(3) 108(4) 36(3)  0(3) −6(2) −3(3) C(11) 36(3) 111(5) 44(3) −4(3) −2(2) −14(3) C(12 46(3) 113(5)38(3) −5(3) −4(3) −15(3) C(13) 36(3) 114(5) 35(3) −5(3) −6(2) −13(3)C(14) 30(3) 108(5) 38(3) −1(3) −1(2)  −2(3) C(15) 47(3) 125(6) 62(4)−7(4) −11(3)   −5(4) C(16) 43(3) 143(6) 65(4) −31(4)  −3(3)  −2(4) C(17)32(3) 103(4) 47(3) −9(3) −10(3)   1(3) C(18) 36(3) 116(5) 51(3) −12(3) −6(3)  −6(3) C(19) 44(3) 154(6) 79(4) −11(4)  −16(3)  −17(4) C(20) 69(4)131(7) 80(4)  1(4) 10(3) −16(4) F(1) 44(2) 186(4) 82(2) 17(2)  1(2) 15(2) F(2) 87(2) 121(3) 53(2)  2(2) −17(2)  −10(2) F(3) 112(3)  116(3)99(3) 29(2) −30(2)  −12(2) N(1) 90(4) 107(5) 91(4) −12(4)  −6(3) −13(4)N(2) 40(3) 135(5) 51(3) −13(3)  −9(2) −21(3) N(3) 31(2) 113(4) 48(3) 1(2) −15(2)   0(2) N(4) 33(2) 107(4) 36(2) −4(2) −3(2) −11(2) O(1)57(2) 122(3) 39(2) −3(2) −15(2)  −13(2)

TABLE 7 Hydrogen coordinates (×10⁴) and isotropic displacementparameters (Å² × 10³) for 1-{(8-anti)-[5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.2.1]oct-3-yl}-2-methylpropan-1-one. x y z U(eq) H(4)39 −3864 −811 99 H(7) 1925 1468 −333 75 H(9A) 84 402 −2058 118 H(9B) −511421 −1328 118 H(9C) −702 160 −1362 118 H(10) 4113 −509 989 71 H(11)2955 175 2112 78 H(12A) 4566 1039 3088 81 H(12B) 4873 −183 2616 81H(13A) 5764 536 974 76 H(13B) 5811 1997 933 76 H(14) 4170 1309 −79 72H(15A) 3061 2769 361 97 H(15B) 4143 3127 1091 97 H(16A) 3288 2527 2203102 H(16B) 2268 2021 1468 102 H(18) 7386 1849 1765 84 H(19A) 8447 26183562 145 H(19B) 9043 2433 2727 145 H(19C) 8576 1277 3175 145 H(20A) 64233745 1687 141 H(20B) 7706 3997 1854 141 H(20C) 7081 4102 2677 141 H(99A)2370(40) −5160(70)  590(50) 160(30) H(99B) 1280(50) −5340(50) −320(30)100(20)

Software and References. SHELXTL, Version 5.1, Bruker AXS, 1997; PLATON,A. L. Spek, J. Appl. Cryst. 2003, 36, 7-13; MERCURY, C. F. Macrae, P. R.Edington, P. McCabe, E. Pidcock, G. P. Shields, R. Taylor, M. Towler andJ. van de Streek, J. Appl. Cryst. 39, 453-457, 2006; OLEX2, Dolomanov,O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H.,(2009). J. Appl. Cryst., 42, 339-341; R. W. W. Hooft et al. J. Appl.Cryst. (2008). 41. 96-103; and H. D. Flack, Acta Cryst. 1983, A39,867-881.

Example 108 Single Crystal X-Ray Analysis of (S)-tert-butyl4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate

(S)-tert-butyl4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylateis the undesired chiral product of step 1 of Example 49. A crystalsuitable for X-ray analysis (a plate with the dimenstions 0.4×0.36×0.48mm⁻¹) was selected from the bulk material by the use of a polarizingmicroscope.

The crystal was mounted on a MiTeGen™ mount with mineral oil anddiffraction data (psi- and omega-scans) were collected at 100 K on aBruker-AXS X8 Kappa diffractometer coupled to an APEX2 CCD detector withCuK_(α) radiation (λ=1.54178 Å) form an 1 μS microsource. Data reductionwas carried out with the program SAINT (Bruker (2011). SAINT, Bruker-AXSInc., Madison, Wis., USA) and semi-imperical absorption correction basedon equivalents was performed with the program SADABS (Sheldrick, G. M.,(2009). SADABS, University of Göttingen, Germany).

The structure was solved by direct methods using SHELXT software suite(Sheldrick, G. M., (2014). SHELXT, University of Göttingen, Germany) inthe space group P2₁, with one target molecule per asymmetric unit. Thestructure was subsequently refined against F² on data with SHELXL(Sheldrick, G. M., Acta Cryst. 2008, A64, 112-122) using establishedrefined techniques (Müller, P., Crystallography Reviews 2009, 15,57-83). All non-hydrogen atoms were found and refined using anisotropicdisplacement parameters.

All carbon-bound hydrogen atoms were placed in geometrically calculatedpositions and refined using a riding model while constraining theirU_(iso) to 1.2 times the U_(eq) of the atoms to which they bind (1.5times for methyl groups). Coordinates for the hydrogen atoms on nitrogenwere taken from the difference Fourier synthesis. Those hydrogen atomswere subsequently refined semi-freely with the help of N—H distancerestraints (target value 0.91 (2) Å) while constraining their U_(iso) to1.2 times the U_(eq) of the corresponding nitrogen atom.

FIG. 2 is an ORTEP Drawing of (S)-tert-butyl4-(5-amino-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate.Pertinent crystal, data collection and refinement are summarized inTable 8. Hydrogen bond parametiers [Å and °] are shown in Table 9.Atomic coordinates, bond lengths, bond angles, torsion angles anddisplacement parameters are listed in Tables 10-13. The diffractiondata, show significant anomalous signal and the absolute structure couldbe established with confidence. The configurations of the chiral carbonatom C10 is S.

TABLE 8 Crystal data and structure refinement for 4-(5-amino-1-methyl-4-(methyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate. Empirical Formula C21 H32 N4O2 Formula weight 372.50 Temperature 1002) K Wavelength 1.54178 ÅCrystal system Monoclinic Space group P2(1) Unit cell dimensions a =6.1660(2) Å; α = 90°. b = 7.1039(2) Å; β = 91.1941(12)°. c = 23.3830(7)Å; γ = 90°. Volume 1024.01(5) Å³ Z 2 Density (calculated) 1.208 Mg/m³Absorption coefficient 0.627 mm⁻¹ F(000) 202 Crystal size 0.480 × 0.360× 0.040 mm³ Theta range for data collection 1.890 to 68.225°. Indexranges −7 <= h <= 7, −8 <= k <= 8, −28 <= l <= 28 Reflections collected37009 Independent reflections 3690 [R(int) = 0.0292] Completeness totheta = 67.679° 100% Absorption correction Semi-empirical formequivalents Max. and min. transmission 0.7531 and 0.6451 Refinementmethod Full-matrix least-squares on F² Data/restraints/parameters3690/3/257 Goodness-of-fit on F² 1.059 Final R indices [I > 2sigma(I)]R1 = 0.0260, wR2 = 0.0672 R indices (all data) R1 = 0.0261, wR2 = 0.0673Absolute structure parameter 0.12(4) Largest diff. peak and hole 0.157and −0.133 e.Å⁻³

TABLE 9 Hydrogen bond parameters for 4-(5-amino-1-methyl-4-(methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-Carboxylate [Å and °]. D-H . . . A d(D-H) d(H .. . A) d(D . . . A) <(DHA) N(1)—H(1B) . . . 0.906(18) 2.391(19) 3.194(2)147.7(17) N(3)#1 C(9)—H(9A) . . . 0.98 2.58 3.487(2) 153.6 N(1)#2C(1)—H(1) . . . 0.95 2.69 3.511(2) 144.6 N(3)#1 C(15)—H(15A) . . . 0.98  2.26 2  .789(2) 112.7 O(1) C(19)—H(19C) . . . 0.98 2.47 3.028(2) 115.7O(1) C(21)—H(21A) . . . 0.98 2.43 2.984(3) 115.0 O(1) Symmetrytransformations used to generate equivalent atoms: #1 −x + 3, y − 1/2,−z + 1 #2 x, y + 1, z

TABLE 10 Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for 4-(5-amino-1-methyl-4-(methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate.U(eq) is defined as one third of the trace of the orthogonalized U^(ij)tensor. x y z U(eq) O(1) 3870(2) 3578(2) 1091(1) 31(1) O(2) 3623(2)6733(2) 1211(1) 27(1) N(1) 11515(2)   803(2) 4835(1) 23(1) N(2)13049(2)  7254(2) 3654(1) 19(1) N(3) 14213(2)  5159(2) 4394(1) 19(1)N(4) 5739(2) 5104(2) 1818(1) 19(1) C(1) 13674(3)  3572(3) 4662(1) 19(1)C(2) 11838(3)  2478(2) 4528(1) 17(1) C(3) 10434(3)  3006(2) 4075(1)17(1) C(4) 10957(3)  4663(2) 3780(1) 16(1) C(5) 10030(3)  5779(2)3315(1) 18(1) C(6) 11348(3)  7318(3) 3269(1) 20(1) C(7) 12835(3) 5654(2) 3971(1) 17(1) C(8) 8474(3) 1816(2) 3945(1) 21(1) C(9) 14616(3) 8735(2) 3774(1) 23(1) C(10) 8079(3) 5407(2) 2928(1) 18(1) C(11) 7544(3)7110(2) 2554(1) 22(1) C(12) 5531(3) 6761(3) 2191(1) 23(1) C(13) 8417(3)3773(2) 2511(1) 19(1) C(14) 6485(3) 3313(2) 2101(1) 19(1) C(15) 7380(3)1905(3) 1665(1) 24(1) C(16) 4603(3) 2414(3) 2422(1) 24(1) C(17) 4350(3)4998(2) 1349(1) 21(1) C(18) 2161(3) 7059(3)  714(1) 23(1) C(19) 3297(3)6539(3)  168(1) 29(1) C(20) 1801(4) 9167(3)  751(1) 35(1) C(21)  60(3)5992(4)  785(1) 36(1)

TABLE 11 Bond lengths [Å] and angles [°] for4-(5-amino-1-methyl-4-(methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate.O(1)—C(17) 1.210(2) C(3)—C(4) 1.406(2) O(2)—C(17) 1.349(2) C(3)—C(8)1.501(2) O(2)—C(18) 1.4739(19) C(4)—C(7) 1.420(2) N(1)—C(2) 1.405(2)C(4)—C(5) 1.453(2) N(1)—H(1A)  0.881(18) C(5)—C(6) 1.368(2) N(1)—H(1B) 0.906(18) C(5)—C(10) 1.513(2) N(2)—C(7) 1.366(2) C(6)—H(6)   0.95N(2)—C(6) 1.369(2) C(8)—H(8A)   0.98 N(2)—C(9) 1.452(2) C(8)—H(8B)  0.98 N(3)—C(1) 1.336(2) C(8)—H(8C)   0.98 N(3)—C(7) 1.337(2)C(9)—H(9A)   0.98 N(4)—C(17) 1.379(2) C(9)—H(9B)   0.98 N(4)—C(12)1.472(2) C(9)—H(9C)   0.98 N(4)—C(14) 1.501(2) C(10)—C(11) 1.525(2)C(1)—C(2) 1.403(2) C(10)—C(13) 1.533(2) C(1)—H(1)   0.95 C(10)—H(10) 1C(2)—C(3) 1.405(2) C(11)—C(12) 1.509(2) C(11)—H(11B)   0.99 C(11)—H(11A)  0.99 C(12)—H(12A)   0.99 C(21)—H(21B)   0.98 C(12)—H(12B)   0.99C(21)—H(21C)   0.98 C(13)—C(14) 1.550(2) C(17)—O(2)—C(18) 121.80(13)C(13)—H(13A)   0.99 C(2)—N(1)—H(1A)  115.4(15) C(13)—H(13B)   0.99C(2)—N(1)—H(1B)  112.0(15) C(14)—C(16) 1.534(2) H(1A)—N(1)—H(1B) 112.5(19) C(14)—C(15) 1.537(2) C(7)—N(2)—C(6) 107.69(14) C(15)—H(15A)  0.98 C(7)—N(2)—C(9) 124.68(14) C(15)—H(15B)   0.98 C(6)—N(2)—C(9)126.96(15) C(15)—H(15C)   0.98 C(1)—N(3)—C(7) 114.08(14) C(16)—H(16A)  0.98 C(17)—N(4)—C(12) 117.01(14) C(16)—H(16B)   0.98 C(17)—N(4)—C(14)118.86(13) C(16)—H(16C)   0.98 C(12)—N(4)—C(14) 116.56(13) C(18)—C(21)1.513(3) N(3)—C(1)—C(2) 124.80(15) C(18)—C(19) 1.515(3) N(3)—C(1)—H(1)117.6 C(18)—C(20) 1.517(3) C(2)—C(1)—H(1) 117.6 C(19)—H(19A)   0.98C(1)—C(2)—C(3) 120.12(15) C(19)—H(19B)   0.98 C(1)—C(2)—N(1) 118.54(15)C(19)—H(19C)   0.98 C(3)—C(2)—N(1) 121.25(15) C(20)—H(20A)   0.98C(2)—C(3)—C(4) 116.74(15) C(20)—H(20B)   0.98 C(2)—C(3)—C(8) 118.91(15)C(20)—H(20C)   0.98 C(4)—C(3)—C(8) 124.34(15) C(21)—H(21A)   0.98C(3)—C(4)—C(7) 117.00(15) C(7)—C(4)—C(5) 105.75(14) C(3)—C(4)—C(5)137.21(15) C(6)—C(5)—C(4) 105.65(14) C(11)—C(10)—C(13) 105.46(12)C(6)—C(5)—C(10) 123.99(15) C(5)—C(10)—H(10) 108.9 C(4)—C(5)—C(10)130.33(15) C(11)—C(10)—H(10) 108.9 C(5)—C(6)—N(2) 111.73(15)C(13)—C(10)—H(10) 108.9 C(5)—C(6)—H(6) 124.1 C(12)—C(11)—C(10)110.94(14) N(2)—C(6)—H(6) 124.1 C(12)—C(11)—H(11A) 109.5 N(3)—C(7)—N(2)123.61(15) C(10)—C(11)—H(11A) 109.5 N(3)—C(7)—C(4) 127.23(15)C(12)—C(11)—H(11B) 109.5 N(2)—C(7)—C(4) 109.17(14) C(10)—C(11)—H(11B)109.5 C(3)—C(8)—H(8A) 109.5 H(11A)—C(11)—H(11B) 108   C(3)—C(8)—H(8B)109.5 N(4)—C(12)—C(11) 112.53(14) H(8A)—C(8)—H(8B) 109.5N(4)—C(12)—H(12A) 109.1 C(3)—C(8)—H(8C) 109.5 C(11)—C(12)—H(12A) 109.1H(8A)—C(8)—H(8C) 109.5 N(4)—C(12)—H(12B) 109.1 H(8B)—C(8)—H(8C) 109.5C(11)—C(12)—H(12B) 109.1 N(2)—C(9)—H(9A) 109.5 H(12A)—C(12)—H(12B) 107.8N(2)—C(9)—H(9B) 109.5 C(10)—C(13)—C(14) 116.15(13) H(9A)—C(9)—H(9B)109.5 C(10)—C(13)—H(13A) 108.2 N(2)—C(9)—H(9C) 109.5 C(14)—C(13)—H(13A)108.2 H(9A)—C(9)—H(9C) 109.5 C(10)—C(13)—H(13B) 108.2 H(9B)—C(9)—H(9C)109.5 C(14)—C(13)—H(13B) 108.2 C(5)—C(10)—C(11) 111.33(14)H(13A)—C(13)—H(13B) 107.4 C(5)—C(10)—C(13) 113.26(13) N(4)—C(14)—C(16)109.86(13) C(16)—C(14)—C(15) 109.79(14) N(4)—C(14)—C(15) 111.79(13)N(4)—C(14)—C(13) 108.56(13) O(2)—C(18)—C(20) 101.41(14)C(16)—C(14)—C(13) 111.37(13) C(21)—C(18)—C(20) 111.21(17)C(15)—C(14)—C(13) 105.41(13) C(19)—C(18)—C(20) 111.07(16)C(14)—C(15)—H(15A) 109.5 C(18)—C(19)—H(19A) 109.5 C(14)—C(15)—H(15B)109.5 C(18)—C(19)—H(19B) 109.5 H(15A)—C(15)—H(15B) 109.5H(19A)—C(19)—H(19B) 109.5 C(14)—C(15)—H(15C) 109.5 C(18)—C(19)—H(19C)109.5 H(15A)—C(15)—H(15C) 109.5 H(19A)—C(19)—H(19C) 109.5H(15B)—C(15)—H(15C) 109.5 H(19B)—C(19)—H(19C) 109.5 C(14)—C(16)—H(16A)109.5 C(18)—C(20)—H(20A) 109.5 C(14)—C(16)—H(16B) 109.5C(18)—C(20)—H(20B) 109.5 H(16A)—C(16)—H(16B) 109.5 H(20A)—C(20)—H(20B)109.5 C(14)—C(16)—H(16C) 109.5 C(18)—C(20)—H(20C) 109.5H(16A)—C(16)—H(16C) 109.5 H(20A)—C(20)—H(20C) 109.5 H(16B)—C(16)—H(16C)109.5 H(20B)—C(20)—H(20C) 109.5 O(1)—C(17)—O(2) 124.46(15)C(18)—C(21)—H(21A) 109.5 O(1)—C(17)—N(4) 125.75(16) C(18)—C(21)—H(21B)109.5 O(2)—C(17)—N(4) 109.78(14) H(21A)—C(21)—H(21B) 109.5O(2)—C(18)—C(21) 110.27(14) C(18)—C(21)—H(21C) 109.5 O(2)—C(18)—C(19)109.91(14) H(21A)—C(21)—H(21C) 109.5 C(21)—C(18)—C(19) 112.43(16)H(21B)—C(21)—H(21C) 109.5

TABLE 12 Anisotropic displacement parameters (Å² × 10³) for 4-(5-amino-1-methyl-4-(methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate. The anisotropic displacement factorexponent takes the form: −2π²[h² a*²U¹¹ + . . . + 2 h k a* b* U¹²]. U¹¹U²² U³³ U²³ U¹³ U¹² O(1) 44(1) 17(1) 31(1) −1(1)  −16(1)  −2(1)  O(2)36(1) 17(1) 27(1) 0(1) −15(1)  2(1) N(1) 23(1) 20(1) 25(1) 6(1) −2(1)−2(1)  N(2) 21(1) 16(1) 21(1) 1(1) −1(1) −5(1)  N(3) 18(1) 18(1) 21(1)−1(1)  −2(1) −1(1)  N(4) 24(1) 14(1) 19(1) 1(1) −3(1) 2(1) C(1) 19(1)19(1) 18(1) 1(1) −2(1) 3(1) C(2) 18(1) 14(1) 19(1) −1(1)   2(1) 1(1)C(3) 16(1) 17(1) 18(1) −1(1)   2(1) 1(1) C(4) 16(1) 16(1) 17(1) −2(1)  1(1) 0(1) C(5) 19(1) 17(1) 18(1) 0(1)  1(1) 1(1) C(6) 23(1) 18(1) 19(1)2(1)  0(1) 1(1) C(7) 18(1) 16(1) 18(1) −1(1)   2(1) −1(1)  C(8) 21(1)18(1) 24(1) 2(1) −1(1) −3(1)  C(9) 27(1) 17(1) 24(1) 0(1)  0(1) −9(1) C(10) 18(1) 17(1) 18(1) 1(1) −1(1) 1(1) C(11) 28(1) 15(1) 22(1) −1(1) −4(1) 3(1) C(12) 30(1) 16(1) 23(1) −3(1)  −6(1) 7(1) C(13) 19(1) 17(1)21(1) 3(1) −1(1) 3(1) C(14) 22(1) 14(1) 20(1) 2(1) −2(1) 2(1) C(15)30(1) 18(1) 24(1) 0(1) −1(1) 2(1) C(16) 22(1) 22(1) 26(1) 5(1) −2(1)−1(1)  C(17) 25(1) 16(1) 22(1) 3(1) −3(1) −1(1)  C(18) 24(1) 24(1) 20(1)3(1) −7(1) 3(1) C(19) 32(1) 27(1) 26(1) 4(1)  1(1) 1(1) C(20) 46(1)28(1) 30(1) −1(1)  −13(1)  15(1)  C(21) 27(1) 50(1) 32(1) 5(1) −1(1)−5(1) 

TABLE 13 Hydrogen coordinates (×10⁴) and isotropic displacementparameters (Å² × 10³) for 4-(5-amino-1-methyl-4-(methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylpiperidine-1-carboxylate. x y z U(eq) H(1A)10150(30) 500(30) 4890(9) 27 H(1B) 12330(30) 760(30) 5162(8) 27 H(1)14601 3153 4965 22 H(6) 11111 8311 3003 24 H(8A) 7582 2425 3647 31 H(8B)7624 1673 4292 31 H(8C) 8936 574 3812 31 H(9A) 14230 9386 4127 34 H(9B)14610 9635 3457 34 H(9C) 16066 8183 3820 34 H(10) 6802 5118 3170 22H(11A) 7318 8225 2800 26 H(11B) 8780 7379 2303 26 H(12A) 4281 6577 244428 H(12B) 5231 7885 1952 28 H(13A) 8766 2629 2737 23 H(13B) 9696 40642278 23 H(15A) 6177 1365 1439 36 H(15B) 8158 896 1869 36 H(15C) 83752556 1411 36 H(16A) 4078 3297 2709 35 H(16B) 5106 1258 2610 35 H(16C)3421 2113 2150 35 H(19A) 4711 7167 160 43 H(19B) 2410 6941 −162 43H(19C) 3504 5172 154 43 H(20A) 1163 9476 1120 52 H(20B) 814 9567 440 52H(20C) 3192 9820 717 52 H(21A) 329 4639 743 55 H(21B) −997 6402 492 55H(21C) −513 6243 1165 55

Software and References. SHELXTL, Version 5.1, Bruker AXS, 1997; PLATON,A. L. Spek, J. Appl. Cryst. 2003, 36, 7-13; MERCURY, C. F. Macrae, P. R.Edington, P. McCabe, E. Pidcock, G. P. Shields, R. Taylor, M. Towler andJ. van de Streek, J. Appl. Cryst. 39, 453-457, 2006; OLEX2, Dolomanov,O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H.,(2009). J. Appl. Cryst., 42, 339-341; R. W. W. Hooft et al. J. Appl.Cryst. (2008). 41. 96-103; and H. D. Flack, Acta Cryst. 1983, A39,867-881.

INCORPORATION BY REFERENCE

All publications, patents and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by reference.

We claim:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt, pharmaceutically activemetabolite, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, wherein, Y is —CF₃; X is phenyl optionallysubstituted with one, two, three, four or five substituentsindependently selected from the group consisting of —CH₃, —CH₂CH₃,—CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃,—F, —Cl, —Br and —CN; R¹ is —CH₃ or —CH₂CH₃; W is

each optionally substituted with one, two, three, four or five —CH₃; andR² is (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl, tetrahydrothiophenyl,thietanyl or indanyl, optionally substituted with one, two, three, fouror five substituents independently selected for each occurrence from thegroup consisting of —F, —Cl, —Br, —OH, (C₁-C₃)alkyl, (C₁-C₃)haloalkyland (C₃-C₁₀)cycloalkyl.
 2. A compound of Formula I:

or a pharmaceutically acceptable salt, pharmaceutically activemetabolite, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, wherein, Y is —CH₃ or —CF₃; X is phenyloptionally substituted with one, two, three, four or five substituentsindependently selected from the group consisting of —CH₃, —CH₂CH₃,—CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃, —F, —Cl,—Br and —CN; R¹ is —CH₃ or —CH₂CH₃; W is

and R² is (C₁-C₅)alkyl, (C₃-C₁₀)cycloalkyl, phenyl,tetrahydrothiophenyl, thietanyl or indanyl, optionally substituted withone, two, three, four or five substituents independently selected foreach occurrence from the group consisting of —F, —Cl, —Br, —OH,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.
 3. A compound ofFormula I:

or a pharmaceutically acceptable salt, pharmaceutically activemetabolite, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, wherein, Y is —CH₃ or —CF₃; X is phenyloptionally substituted with one, two, three, four or five substituentsindependently selected from the group consisting of —CH₃, —CH₂CH₃,—CH₂OH, —OH, —OCH₃, —SCH₃, —OCH₂CH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₃, —F, —Cl,—Br and —CN; R¹ is —CH₃ or —CH₂CH₃; W is

and R² is (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl,tetrahydrothiophenyl, thietanyl or indanyl, optionally substituted withone, two, three, four or five substituents independently selected foreach occurrence from the group consisting of —F, —Cl, —Br, —OH,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.
 4. The compoundof claim 1, 2, or 3, wherein R² (C₁-C₆)alkyl optionally substituted withone, two, three, four or five substituents independently selected foreach occurrence from the group consisting of —F, —Cl, —Br, —OH,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl and (C₃-C₁₀)cycloalkyl.
 5. The compoundof claim 1, 2, or 3, wherein R² is (C₁-C₆)alkyl.
 6. The compound ofclaim 1, 2, or 3, wherein R² is methyl substituted with(C₃-C₅)cycloalkyl.
 7. The compound of claim 1, 2, or 3, wherein R² isethyl substituted with —CF₃.
 8. The compound of claim 1, 2, or 3,wherein R² is ethyl substituted with —OH and —CF₃.
 9. A compoundselected from the group consisting of

and pharmaceutically acceptable salts thereof.
 10. The compound of claim1 wherein the compound is

or a pharmaceutically acceptable salts thereof.
 11. A compound havingthe structure:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a compound according to claim 1, 2 or 3, or apharmaceutically acceptable salt, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, admixed with a pharmaceutically acceptable carrier,excipient or dilutant.
 14. A method of inhibiting RORC2 comprising ofadministering to a patient an effective amount of a pharmaceuticalcomposition of claim 13.